FENG XUEYANG (US)
WORKENTINE MATTHEW (CA)
EPIMERON USA INC (US)
What is claimed is: 1. A recombinant host cell which produces Δ9-tetrahydrocannabinolic acid (THCA) when cultured in the presence of hexanoic acid (HA) or olivetolic acid (OA), wherein the cell comprises a pathway of enzymes capable of producing cannabigerolic acid (CBGA) and a nucleic acid encoding an N-terminal secretion peptide linked to a polypeptide having THCAS activity, wherein the N-terminal secretion peptide comprises an amino acid sequence selected from SEQ ID NO: 78, 86, 88, 90, 92, 72, and 84. 2. The cell of claim 1, wherein: (a) the source organism of the recombinant host cell is selected from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, and Escherichia coli; (b) the polypeptide having THCAS activity comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 18; (c) the N-terminal secretion peptide linked to the polypeptide having THCAS activity comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 124, 126, 128, 130, 132, 134, and 136; (d) the amount of THCA produced by the cell when cultured in the presence of HA or OA is increased relative to a control host cell comprising a pathway of enzymes AAE, TKS, OAC, and PT4, and a nucleic acid encoding an N-terminal secretion peptide linked to a polypeptide having THCAS activity comprising an amino acid sequence of SEQ ID NO: 122; and/or (e) the cell also produces cannabidiolic acid (CBDA), and/or cannabichromenic acid (CBCA). 3. A recombinant host cell which produces cannabidiolic acid (CBDA) when cultured in the presence of hexanoic acid (HA) or olivetolic acid (OA), wherein the cell comprises a pathway of enzymes capable of producing cannabigerolic acid (CBGA) and a nucleic acid encoding an N-terminal secretion peptide linked to a polypeptide having CBDAS activity, wherein the N-terminal secretion peptide comprises an amino acid sequence selected from SEQ ID NO: 78, 86, 88, 70, and 72. 4. The cell of claim 3, wherein: (a) the source organism of the recombinant host cell is selected from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, and Escherichia coli; (b) the polypeptide having CBDAS activity comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 16 or SEQ ID NO: 20; (c) the N-terminal secretion peptide linked to the polypeptide having CBDAS activity 108, 110, 112, 114, and 46; (d) the amount of CBDA produced by the cell when cultured in the presence of HA or OA is increased relative to a control host cell comprising a pathway of enzymes AAE, TKS, OAC, and PT4, and a nucleic acid encoding an N-terminal secretion peptide linked to a polypeptide having CBDAS activity comprising an amino acid sequence of SEQ ID NO: 44; and/or (e) the cell also produces Δ9-tetrahydrocannabinolic acid (THCA), and/or cannabichromenic acid (CBCA). 5. The cell of any one of claims 1-4, wherein: (a) the pathway of enzymes is capable of catalyzing reactions (i) – (iv): (i) O O H3 , and (iv) COOH 3 ; nd PT4; and/or (c) the pathway of enzymes comprises (i) AAE having an amino acid sequence of at least 90% identity to SEQ ID NO: 2; (ii) TKS having an amino acid sequence of at least 90% identity to SEQ ID NO: 4; (iii) OAC having an amino acid sequence of at least 90% identity to SEQ ID NO: 6; and (iv) PT4 having an amino acid sequence of at least 90% identity to SEQ ID NO: 8 or 10. 6. A method for producing a cannabinoid selected from cannabidiolic acid (CBDA), Δ9- tetrahydrocannabinolic acid (THCA), and/or cannabichromenic acid (CBCA), the method comprising: (a) culturing in a suitable medium comprising hexanoic acid (HA) or olivetolic acid (OA) and a recombinant host cell of any one of claims 1-5; and (b) recovering the produced cannabinoid. 7. A recombinant polypeptide having cannabinoid synthase activity, wherein the polypeptide comprises an amino acid sequence of at least 85% identity to SEQ ID NO: 14 and comprises at least one amino acid residue difference relative to SEQ ID NO: 14 selected from: T47S, S89A, I102V, R109H, V135I, L144F, A145P, A146G, C152G, A153V, G158S, P164A, H186D, L203I, A208G, S210N, V215A, R220K, M229I, I235N, E240G, V245F, K447Q, and R516H. 8. The recombinant polypeptide of claim 7, wherein the amino acid sequence has at least 90% identity to SEQ ID NO: 14 and the following amino acid residue differences relative to SEQ ID NO: 14: T47S, S89A, I102V, R109H, V135I, L144F, A145P, A146G, C152G, A153V, G158S, P164A, H186D, L203I, A208G, S210N, V215A, R220K, M229I, I235N, E240G, V245F, K447Q, and R516H. identity to SEQ ID NO: 20. 10. The polypeptide of any one of claims 7-9, wherein the polypeptide has cannabinoid synthase activity capable of converting cannabigerolic acid (CBGA) to cannabidiolic acid (CBDA), and/or Δ9-tetrahydrocannabinolic acid (THCA). 11. The polypeptide of any one of claims 7-10, wherein the polypeptide further comprises N- terminal secretion peptide comprising an amino acid sequence selected from SEQ ID NO: 86, 88, 90, 92, 70, 72, 78, and 84. 12. A recombinant polypeptide comprising an N-terminal secretion peptide linked to a polypeptide having CBDAS activity, wherein the N-terminal secretion peptide comprises an amino acid sequence selected from SEQ ID NO: 86, 88, 90, 92, 72, 78, and 84. 13. The polypeptide of claim 12, wherein the N-terminal secretion peptide linked to the polypeptide comprises an amino acid sequence having at least 90% identity to any one of SEQ ID NO: 94, 96, 98, 108, 110, 112, and 114. 14. The polypeptide of claim 12, wherein the polypeptide comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 20. 15. The polypeptide of claim 14, wherein the N-terminal secretion peptide linked to the polypeptide comprises an amino acid sequence having at least 90% identity to any one of SEQ ID NO: 108, 110, 112, and 114. 16. A recombinant polypeptide comprising an N-terminal secretion peptide linked to a polypeptide having THCAS activity, wherein the N-terminal secretion peptide comprises an amino acid sequence selected from SEQ ID NO: 78, 86, 88, 90, 92, 72, and 84. 17. The polypeptide of claim 16, wherein the N-terminal secretion peptide linked to the polypeptide comprises an amino acid sequence having at least 90% identity to any one of SEQ ID NO: 124, 126, 128, 130, 132, 134, and 136 18. The polypeptide of claim 16, wherein the polypeptide comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 18. 19. A polynucleotide encoding a recombinant polypeptide of any one of claims 7-18. 20. An expression vector comprising a polynucleotide of claim 19. |
[0074] In at least one embodiment, the compositions and methods of the present disclosure can be used for the production of the varin series of cannabinoids, CBGVA, Δ 9 -THCVA, CBDVA, and CBCVA. As shown in Table 2, the varin cannabinoids feature a 3 carbon propyl side-chain rather than the 5 carbon pentyl side chain found in the common cannabinoids, CBGA, THCA, CBDA, and CBCA. An exemplary cannabinoid pathway capable of producing the rare naturally occurring cannabinoid, cannabigerovarinic acid (CBGVA), is depicted in FIG. 3. Instead of starting with hexanoic acid, the pathway of FIG.3 is fed butyric acid (BA) which is converted to divarinic acid (DA) via the same three enzyme pathway of AAE, TKS, and OAC. The precursor DA is then converted by PT4 to the rare cannabinoid, CBGVA. Accordingly, in at least one embodiment of the recombinant host cell, the pathway capable of producing a cannabinoid comprises enzymes capable of catalyzing reactions (i) – (iv): (i) O O H 3 , OH O O O O COOH H 3 . and (iv) OH COOH CH 3 OH COOH H 3 P P . [0075] As shown in FIG.3, exemplary enzymes capable of catalyzing reactions (i) – (iv) are: (i) acyl activating enzyme (AAE); (ii) tetraketide synthase (TKS); (iii) olivetolic acid cyclase (OAC); and (iv) aromatic prenyltransferase (PT4). Exemplary enzymes, AAE, TKS, OAC, and PT4 derived from C. sativa are known in the art and also provided in Table 1 and the accompanying Sequence Listing. [0076] As further illustrated in FIG.4, the heterologous pathway depicted in FIG.3 which is capable of producing a rare cannabinoid, such as CBGVA, can be further modified to include one or more cannabinoid synthase enzymes (e.g., CBDAS, THCAS, CBCAS). As shown by the exemplary pathway of FIG.4, with the incorporation of one or more synthase enzymes, the rare varin cannabinoid, CBGVA, can be converted to the rare varin cannabinoids, cannabidivarinic acid (CBDVA), Δ 9 -tetrahydrocannabivarinic acid (Δ 9 -THCVA), and cannabichromevarinic acid (CBCVA). Enzymes capable of carrying out these conversions include the C. sativa CBDA synthase, THCA synthase, and CBCA synthase, respectively. Accordingly, in at least one embodiment, the present disclosure provides a recombinant host cell comprising a pathway capable of converting BA to CBGVA and further comprising an enzyme capable of catalyzing the conversion of (v) CBGVA to Δ 9 -THCVA; (vi) CBGVA to CBDVA; and/or (vii) CBGVA to CBCVA. Thus, in at least one embodiment, the recombinant host cell comprises pathway capable of converting BA to CBGVA further comprises further comprises enzymes capable of catalyzing a reaction (v), (vi), and/or (vii): (v) 3 COOH H 3 THCVA) , (vi) CH 3 H 3 , (vii) CH 3 OH COOH H C OH H 3 . [0077] Exemplary enzymes capable of catalyzing reaction (v)-(vii) as shown above are: (v) THCA synthase (THCAS); (vi) CBDA synthase (CBDAS); and (vii) CBCA synthase (CBCAS). Exemplary THCAS, CBDAS, and CBCAS enzymes are provided in Table 1. [0078] Furthermore, as shown in FIG.4, the rare cannabinoid acids, CBDVA, Δ 9 -THCVA, and CBCVA, can undergo a further decarboxylation reaction to provide the varin cannabinoid products, cannabidivarin (CBDV), Δ 9 -tetrahydrocannabivarin (Δ 9 -THCV), and cannabichromevarin (CBCV), respectively. In some embodiments, this further decarboxylation can be carried out under in vitro reaction conditions using the cannabinoid acids isolated from the recombinant host cells. [0079] As shown by the pathways depicted in FIGS.1 and 3, a heterologous cannabinoid pathway comprising the sequence of at least the three enzymes AAE, TKS, and OAC, is capable of converting a precursor substrate compound, such as hexanoic acid (HA) to the cannabinoid precursor compound, such as olivetolic acid (OA). Accordingly, it is contemplated that a heterologous cannabinoid pathway of the present disclosure can be used to produce a cannabinoid precursor compound. Such precursor compounds can be useful products, and/or can be used to prepare other derivative compounds, either synthetically or biosynthetically. Other cannabinoid precursor compounds, or derivatives that can be produced by such a three- polyketide derivatives, and others known in the art (see e.g., Elsohly and Slade, Life Sci.2005 Dec.22; 78(5):539-48. Epub 2005 Sep.30; Bow, E. W. and Rimoldi, J. M., “The Structure- Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation,” Perspectives in Medicinal Chemistry 2016:817-39 doi: 10.4137/PMC.S32171.) In at least one embodiment, a cannabinoid precursor compound, such as OA or divarinic acid (DA), can be produced, and then further modified or derivatized using an in vitro enzymatic biosynthesis, using e.g., a cannabinoid synthase. [0080] Similarly, as shown in FIG.1 and 3, a heterologous cannabinoid pathway comprising the sequence of at least the four enzymes AAE, TKS, OAC, and PT4, is capable of converting a precursor substrate compound, such as hexanoic acid (HA) to an initial cannabinoid compound, such as cannabigerolic acid (CBGA) or CBGVA. These initial cannabinoid product compounds can themselves be used as a substrate for the in vitro biosynthesis of a range of further cannabinoid product compounds, such as THCA and THCVA, as shown in FIGS.2 and 4. A wide range of cannabinoid compounds, such as those shown in Table 2, are contemplated for in vivo biosynthetic production in a recombinant host cell of the present disclosure or via a partial or full in vitro biosynthesis process using recombinant polypeptides of the present disclosure. [0081] As described herein, the heterologous cannabinoid pathways of the present disclosure can be incorporated (e.g., by recombinant transformation) into a range of host cells to provide a system for biosynthetic production of cannabinoids (e.g., CBGA, CBDA, THCA, CBCA) or cannabinoid precursor compounds. Generally, the host cell used in the recombinant host cells of the present disclosure can be any cell that can be recombinantly modified with nucleic acids and cultured to express the recombinant products of those nucleic acids, including polypeptides and metabolites produced by the activity of the recombinant polypeptides. A wide range of suitable sources of host cells are known in the art, and exemplary host cell sources useful as recombinant host cells of the present disclosure include, but are not limited to, Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, and Escherichia coli. It is also contemplated that the host cell source for a recombinant host cell of the present disclosure can include a non- naturally occurring cell source, e.g., an engineered host cell. For example, a non-naturally occurring source host cell, such as a yeast cell previously engineered for improved production of recombinant genes, may be used to prepare the recombinant host cell of the present disclosure. Accordingly, in at least one embodiment, the present disclosure provides a recombinant host cell transformed with a cannabinoid biosynthesis pathway and a heterologous nucleic acid encoding a protein that is not part of the pathway, wherein the host cell source is selected from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, Escherichia coli, or an engineered cell derived from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, Escherichia coli. acids encoding a pathway of enzymes capable of producing the cannabinoid, CBGA, and a heterologous nucleic acid comprising a sequence encoding a polypeptide having CBDAS and/or THCAS activity. As described elsewhere herein, nucleic acid sequences encoding the cannabinoid pathway enzymes, are known in the art and provided herein, and can readily be used in accordance with the present disclosure. Typically, the nucleic acid sequence encoding enzymes which form a part of a cannabinoid pathway, further include one or more additional nucleic acid sequences, for example, a nucleic acid sequence controlling expression of the proteins which form a part of a cannabinoid biosynthetic enzyme pathway, and these one or more additional nucleic acid sequences together with the nucleic acid sequence encoding a protein which form a part of an cannabinoid biosynthetic enzyme pathway can be considered a heterologous nucleic acid sequence. A variety of techniques and methodologies are available and well known in the art for introducing heterologous nucleic acid sequences, such as nucleic acid sequences encoding the cannabinoid pathway enzymes (e.g., CBDA synthase), into a host cell so as to attain expression the host cell. Such techniques are well known to the skilled artisan and can, for example, be found in Sambrook et al., Molecular Cloning, a Laboratory Manual, Cold Spring Harbor Laboratory Press, 2012, Fourth Ed. [0083] One of ordinary skill will recognize that the heterologous nucleic acids encoding the recombinant CBDA synthase enzymes and associated N-terminal secretion peptides (or other pathway enzymes) will further comprise transcriptional promoters capable of controlling expression of the enzymes in the recombinant host cell. [0084] Generally, the transcriptional promoters are selected to be compatible with the host cell, so that promoters obtained from bacterial cells are used when a bacterial host cell is selected in accordance herewith, while a fungal promoter is used when a fungal host cell is selected, a plant promoter is used when a plant cell is selected, and so on. Promoters useful in the recombinant host cells of the present disclosure may be constitutive or inducible, provided such promoters are operable in the host cells. Promoters that may be used to control expression in fungal host cells, such as Saccharomyces cerevisiae, are well known in the art and include, but are not limited to: inducible promoters, such as a Gal1 promoter or Gal10 promoter, a constitutive promoter, such as an alcohol dehydrogenase (ADH) promoter, a glyceraldehyde-3-phosphate dehydrogenase (GPD) promoter, or an S. pombe Nmt, or ADH promoter. Exemplary promoters that may be used to control expression in bacterial cells can include the Escherichia coli promoters lac, tac, trc, trp or the T7 promoter. Exemplary promoters that may be used to control expression in plant cells include, for example, a Cauliflower Mosaic Virus 35S promoter (Odell et al. (1985) Nature 313:810-812), a ubiquitin promoter (U.S. Pat. No.5,510,474; Christensen et al. (1989)), or a rice actin promoter (McElroy et al. (1990) Plant Cell 2:163-171). Exemplary promoters that can be used in mammalian cells include, a viral promoter such as an SV40 promoter or a metallothionine promoter. All of these Further nucleic acid control elements useful for controlling expression in a recombinant host cell can include transcriptional terminators, enhancers and the like, all of which may be used with the heterologous nucleic acids incorporate in the recombinant host cells of the present disclosure. [0085] A wide variety of techniques are well known in the art for linking transcriptional promoters and other control elements to heterologous nucleic acid sequences encoding pathway genes. Such techniques are described in e.g., Sambrook et al., Molecular Cloning, a Laboratory Manual, Cold Spring Harbor Laboratory Press, 2012, Fourth Ed. [0086] Accordingly, in at least one embodiment, the heterologous nucleic acid sequences of the present disclosure comprise a promoter capable of controlling expression in a host cell, wherein the promoter is linked to a nucleic acid sequence encoding an AAE enzyme, and, as necessary, other enzymes constituting a cannabinoid pathway (e.g., TKS, OAC, PT4, CBDAS). This heterologous nucleic acid sequence can be integrated into a recombinant expression vector which ensures good expression in the desired host cell, wherein the expression vector is suitable for expression in a host cell, meaning that the recombinant expression vector comprises the heterologous nucleic acid sequence linked to any genetic elements required to achieve expression in the host cell. Genetic elements that may be included in the expression vector in this regard include a transcriptional termination region, one or more nucleic acid sequences encoding marker genes, one or more origins of replication, and the like. In some embodiments, the expression vector further comprises genetic elements required for the integration of the vector or a portion thereof in the host cell's genome. [0087] It is also contemplated that in some embodiments an expression vector comprising a heterologous nucleic acid of the present disclosure may further contain a marker gene. Marker genes useful in accordance with the present disclosure include any genes that allow the distinction of transformed cells from non-transformed cells, including all selectable and screenable marker genes. A marker gene may be a resistance marker such as an antibiotic resistance marker against, for example, kanamycin or ampicillin. Screenable markers that may be employed to identify transformants through visual inspection include β-glucuronidase (GUS) (U.S. Pat. Nos.5,268,463 and 5,599,670) and green fluorescent protein (GFP) (Niedz et al., 1995, Plant Cell Rep., 14: 403). [0088] Recombinant Polypeptides with Enhanced Cannabinoid Synthase Activity [0089] The present disclosure provides recombinant host cells (e.g., S. cerevisiae) that comprise a functional pathway capable of production of a cannabinoid CBGA and further comprising a recombinant polypeptide having CBDA synthase (CBDAS) activity capable of converting CBGA to CBDA, and in some cases, also THCA synthase (THCAS) activity, capable CBGA to CBCA. [0090] In at least one embodiment, the recombinant host cell comprises a cannabinoid pathway that includes at least the enzymes AAE, OAC, TKS, and PT4, and a recombinant polypeptide having a cannabinoid synthase (CBDAS, THCAS, and/or CBCAS) activity, wherein the polypeptide is a homolog of the CBDAS of SEQ ID NO: 12 from C. sativa comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 12. [0091] A library of 12 homologs of the d28_CBDAS polypeptide of SEQ ID NO: 14 was generated by bioinformatics analysis of C. sativa and related genome databases. The library of CBDAS homologs along with their nucleotide and amino acid sequences are disclosed below in Table 3, as well as in the accompanying Sequence Listing. Also disclosed in Table 3 are the sequences of the d28_CBDAS and the 12 CBDAS homologs fused with the N-terminal yeast secretion peptide, SP-Alpha (SEQ ID NO: 70), and the sequences of a library of secretion peptides and their N-terminal fusions with d28_CBDAS, the homolog, CBDAS_Var95, and the THCA synthase polypeptide d28_THCAs of SEQ ID NO: 18. [0092] TABLE 3 SEQ SEQ ID ID DCKQLSWIDTIIFYSGVVNYNTTYFKKEILLDRSGGRKAAFSIKLDYVKKPI PNNYTQARIWGEKYFGKNFNRLVKVKTKVDP NEKHLNWIRNIYNFMTPYVSKNPRLAYLNYRDLDIGINDPKNPNNYTQARIW MRNYGLAADNIIDAHLVNVDGKVLDRKSMGEDLFWAIRGGGGENFGIIAAWK WGEKYFGKNFNRLVKVKTKVDPDNFFRNEQSIPPLPLRHH Alpha-factor full DFDVAVLPFSNSTNNGLLFINTTIASIAAKEEGVSLEKREAEA FRNEQSIPPLPRHRH RNEQSIPPLPRHRH PRLAYLNYRDLDIGINDPKNPNNYTQARIWGEKYFGKNFDRLVKVKTLVDPN ISESAIPFPHRAGIMYELWYTASWEKQEDNEKHINWVRSVYNFTTPYVSQNP SAIPFPHRAGIMYELWYTASWEKQEDNEKHINWVRSVYNFTTPYVSQNPRLA y q g . . , synthase, CBDAS_Var95 (SEQ ID NO: 20) has an amino acid sequence that has 95% sequence identity to CBDAS synthase d28_CBDAS (SEQ ID NO: 14) of C. sativa, and 89% sequence identity to the THCAS synthase d28_THCAS (SEQ ID NO: 18) of C. sativa. As described elsewhere herein, the CBDAS_Var95 (SEQ ID NO: 20) enzyme when engineered in a cannabinoid pathway is capable of producing CBDA, THCA, and CBCA (see Example 1). CBDAS_Var95 represents a surprising polypeptide having cannabinoid synthase activity and a chimeric amino acid sequence structure not previously known in the art. [0094] Accordingly, in at least one embodiment, the present disclosure also provides a recombinant polypeptide having CBDA synthase activity, wherein the polypeptide comprises an amino acid sequence of at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the naturally occurring d28_CBDAS of SEQ ID NO: 14 and also comprises at least one of the amino acid residue differences relative to SEQ ID NO: 14 found in the sequence of SEQ ID NO: 20 (CBDAS_Var95). This includes any one or more the following amino acid differences: T47S, S89A, I102V, R109H, V135I, L144F, A145P, A146G, C152G, A153V, G158S, P164A, H186D, L203I, A208G, S210N, V215A, R220K, M229I, I235N, E240G, V245F, K447Q, and R516H. In at least one embodiment, the polypeptide can comprise an amino acid sequence of at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO: 14 and all of the amino acid residue differences relative to SEQ ID NO: 14 found in the sequence of SEQ ID NO: 20. [0095] In at least one embodiment, the present provides a recombinant polypeptide having CBDA synthase activity wherein the polypeptide comprises an amino acid sequence of at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO: 20, wherein the amino acid sequence includes one or more amino acid differences relative to SEQ ID NO: 14 selected from: T47S, S89A, I102V, R109H, V135I, L144F, A145P, A146G, C152G, A153V, G158S, and R516H. [0096] As noted above, it is surprising feature of CBDAS_Var95 of SEQ ID NO: 20 that it has THCAS activity and converts CBGA to THCA despite having only 89% amino acid sequence identity to the C. sativa THCAS of SEQ ID NO: 18 and the following 59 amino acid differences relative to SEQ ID NO: 18: K13Q, H14Y, V19A, A20T, P22L, H29N, D30N, Q31P, I36V, Q42H, I47S, N62H, N63V, A68G, V261L, K269R, H275Q, T281A, V282I, G284T, I289V, H291L, K316R, E317Q, F318L, T324I, F333Y, N334D, A336D, K339N, K350Q, K351N, K352G, S355K, T368S, A369V, M370F, K372Q, V382I, V388A, E397D, M413L, T419I, A420C, I432L, V435I, S437N, V438I, T442M, L462I, K464I, T465N, N466D, H467P, A468K, S469N, N489D, K497L, P515R. Accordingly, in at least one embodiment, the present disclosure also provides a recombinant polypeptide with THCA synthase activity, wherein the polypeptide comprises an amino acid sequence of at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the naturally occurring d28_THCAS of SEQ ID NO: 18 and also comprises at least one of the amino acid residue differences relative to SEQ ID NO: 18 found in the sequence of SEQ ID NO: 20 (CBDAS_Var95). This includes any one or more the following amino acid differences: K13Q, H14Y, V19A, A20T, P22L, H29N, D30N, Q31P, I36V, Q42H, I47S, N62H, N63V, A68G, V261L, K269R, H275Q, T281A, V282I, G284T, I289V, H291L, K316R, E317Q, F318L, T324I, F333Y, N334D, A336D, K339N, K350Q, K351N, K352G, S355K, T368S, A369V, M370F, K372Q, V382I, V388A, E397D, M413L, T419I, A420C, I432L, V435I, S437N, V438I, T442M, L462I, K464I, T465N, N466D, H467P, A468K, S469N, N489D, K497L, P515R. In at least one embodiment, the polypeptide can comprise an amino acid sequence of at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO: 18 and all of the amino acid residue differences relative to SEQ ID NO: 18 found in the sequence of SEQ ID NO: 20. [0097] In at least one embodiment, the present disclosure provides a recombinant polypeptide having THCA synthase activity wherein the polypeptide comprises an amino acid sequence of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NO: 20, wherein the amino acid sequence includes one or more amino acid differences relative to SEQ ID NO: 18 selected from: K13Q, H14Y, V19A, A20T, P22L, H29N, D30N, Q31P, I36V, Q42H, I47S, N62H, N63V, A68G, V261L, K269R, H275Q, T281A, V282I, G284T, I289V, H291L, K316R, E317Q, F318L, T324I, F333Y, N334D, A336D, K339N, K350Q, K351N, K352G, S355K, T368S, A369V, M370F, K372Q, V382I, V388A, E397D, M413L, T419I, A420C, I432L, V435I, S437N, V438I, T442M, L462I, K464I, T465N, N466D, H467P, A468K, S469N, N489D, K497L, P515R. [0098] As described elsewhere herein, the recombinant CBDAS synthase polypeptides of even-numbered SEQ ID NOs: 20-42 were modified with an N-terminal linked yeast secretion engineered yeast host cells that produce CBGA, to further convert the CBGA to one or more of the cannabinoid compounds, CBDA, CBCA, or THCA. Recombinant polynucleotide constructs encoding the SP-Alpha-CBDAS homolog polypeptides (even-numbered SEQ ID NOs: 46-68) were synthesized and cloned under control of the Gal1 promoter. The 12 recombinant CBDA synthase homolog constructs (odd-numbered SEQ ID NOs: 45-67) were integrated into the genome of a Saccharomyces cerevisiae strain already comprising a cannabinoid pathway capable of biosynthesizing CBGA. As described in elsewhere herein (e.g., Example 1) the library variants were cultured in rich media and screened using LC/MS for cannabinoid synthase activity capable of producing, CBDA, THCA, and/or CBCA. [0099] Pooled screening of the transformed yeast strains followed by sequencing identified at least 3 of the 12 putative CBDAS homologs modified with the yeast secretion peptide SP- Alpha were capable of producing CBDA, THCA, and/or CBCA from either HA or OA feedstock. Moreover, the yeast strains capable of producing CBGA from HA or OA when transformed with the variant CBDAS homolog “CBDAS_Var95” (polypeptide of SEQ ID NO: 20 or SEQ ID NO: 46 with SP-Alpha) were able to produce all three cannabinoids, CBDA, THCA, and CBCA. This indicates that CBDAS_Var95 exhibits CBDAS activity in converting CBGA to CBDA, as well as THCAS activity, and CBCAS activity. Additionally, two other of the 12 putative CBDAS homologs, “Cs10_4” and “CBDAS2” (SEQ ID NO: 22 and 24) when recombinantly transformed in the yeast strains capable of producing CBGA from OL were found to exhibit production of the cannabinoid, CBCA, but not CBDA or THCA. [00100] Based on what is known regarding the relatively high level of production of the cannabinoids, CBDA or THCA, in the trichome cells of the C. sativa plant, it is believed that production of these cannabinoids in a recombinant host cell (e.g., yeast) may depend on proper secretion of the CBDA synthase or THCA synthase enzyme that converts CBGA to CBDA and CBGA to THCA, respectively. In order to further explore enhanced in vivo CBDA and THCA production from recombinantly transformed yeast, a range of secretion peptide fusions of the CBDA synthase, “d28_CBDAS” (SEQ ID NO: 14), the CBDAS homolog “CBDAS_Var95” (SEQ ID NO: 20), and the THCA synthase, “d28_THCAS” (SEQ ID NO: 18), were constructed and screened as described in the Examples. It is a surprising technical effect of the present disclosure that the secretion peptides SP_AA (SEQ ID NO: 72), SP_AT (SEQ ID NO: 78), SP_IV (SEQ ID NO: 86), and SP_KP (SEQ ID NO: 88) when combined as N-terminal fusions with these CBDAS and THCAS polypeptides and integrated into yeast strains capable of producing CBGA resulted in enhanced production of CBDA or THCA. Additionally, the secretion peptides SP_IN (SEQ ID NO: 84), SP_LZ (SEQ ID NO: 90), or SP_SA (SEQ ID NO: 92) when combined as N-terminal fusions with d28_THCAS polypeptide and integrated into a yeast strain capable of producing CBGA resulted in enhanced production of THCA. THCA by a recombinant host cell with the integration of secretion peptide constructs of the cannabinoid synthases of CBDAS of SEQ ID NO: 14 or 20, or a THCAS of SEQ ID NO: 18 into a heterologous cannabinoid pathway, provides a distinct and unexpected advantage of these recombinant host cells for use in the production of the cannabinoids, CBDA and/or THCA. [0101] In at least one embodiment, a recombinant host cell capable of producing CBGA and further comprising a recombinant SP-CBDAS construct, wherein the SP is selected from SP_AA (SEQ ID NO: 72), SP_AT (SEQ ID NO: 78), SP_IV (SEQ ID NO: 86), and SP_KP (SEQ ID NO: 88), and is capable of producing CBDA with a titer that is increased relative to a control recombinant host cell comprising the same cannabinoid biosynthesis pathway but with an SP- CBDAS construct wherein the SP is SP-Alpha of SEQ ID NO: 70. In at least one embodiment, the titer of CBDA produced by the host cell is increased by at least 1.1-fold.1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 10-fold, or more relative to the SP-Alpha- CBDAS control recombinant host cell. [0102] In at least one embodiment, a recombinant host cell capable of producing CBGA and further comprising a recombinant SP-THCAS construct, wherein the SP is selected from SP_AA (SEQ ID NO: 72), SP_AT (SEQ ID NO: 78), SP_IV (SEQ ID NO: 86), and SP_KP (SEQ ID NO: 88), SP_IN (SEQ ID NO: 84), SP_LZ (SEQ ID NO: 90), or SP_SA (SEQ ID NO: 92), is capable of producing THCA with a titer that is increased relative to a control recombinant host cell comprising the same cannabinoid biosynthesis pathway but with an SP-THCAS construct wherein the SP is SP-Alpha of SEQ ID NO: 70. In at least one embodiment, the titer of THCA produced by the host cell is increased by at least 1.1-fold.1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold, 6-fold, 10-fold, or more relative to the SP-Alpha-THCAS control recombinant host cell. [0103] In at least one embodiment, the present disclosure also provides a recombinant host cell comprising a pathway capable of producing CBGA, wherein the pathway comprises the enzymes AAE, TKS, OAC, and PT4, and a SP-CBDAS construct integrated into the host cell that encodes an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to any one of SEQ ID NO: 44, 46, 94, 96, 98, 108, 110, 112, and 114. In at least one embodiment, the SP-CBDAS polypeptide comprises an amino acid sequence of any one of SEQ ID NO: 44, 46, 94, 96, 98, 108, 110, 112, and 114. In at least one embodiment, the SP-CBDAS construct comprises a nucleic acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to any one of SEQ ID NO: 43, 45, 93, 95, 97, 107, 109, 111, and 113. In at least one embodiment, the SP-CBDAS construct comprises a polynucleotide sequence of any one of SEQ ID NO: 43, 45, 93, 95, 97, 107, 109, 111, and 113. [0104] In at least one embodiment, the present disclosure also provides a recombinant host cell comprising a pathway capable of producing CBGA, wherein the pathway comprises the that encodes an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to any one of SEQ ID NO: 122, 124, 126, 128, 130, 132, 134, and 136. In at least one embodiment, the SP-THCAS polypeptide comprises an amino acid sequence of any one of SEQ ID NO: 122, 124, 126, 128, 130, 132, 134, and 136. In at least one embodiment, the SP-THCAS construct integrated in the host cell comprises a nucleic acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to any one of SEQ ID NO: 121, 123, 125, 127, 129, 131, 133, and 135, and 139. In at least one embodiment, the SP-THCAS construct comprises a nucleotide sequence of any one of SEQ ID NO: 121, 123, 125, 127, 129, 131, 133, and 135. [0105] In at least one embodiment, the polynucleotide sequence of the nucleic acid encoding the heterologous cannabinoid pathway in the recombinant host cell is codon-optimized for expression in a recombinant host cell, wherein the host cell source is selected from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, Escherichia coli, or an engineered cell derived from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, Escherichia coli. [0106] In at least one embodiment, the present disclosure provides an isolated nucleic acids, wherein the nucleic acid encodes a pathway comprising the enzymes AAE, TKS, OAC, and PT4, and a recombinant CBDAS homolog or SP-CBDAS polypeptide of the present disclosure, wherein the portion of the nucleic acid encoding the CBDAS enzyme comprises a nucleotide sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to any one of SEQ ID NOs: 19, 21, 23, 25, 43, 45, 47, 49, 93, 95, 97, 107, 109, 111, and 113. In at least one embodiment, the nucleic acid encoding the pathway comprising the enzymes AAE, TKS, OAC, PT4, and a recombinant CBDAS homolog or SP- CBDAS polypeptide, the portion of the nucleic acid encoding the recombinant CBDAS homolog or SP-CBDAS polypeptide comprises a nucleotide sequence of any one of SEQ ID NOs: 19, 21, 23, 25, 43, 45, 47, 49, 93, 95, 97, 107, 109, 111, and 113. [0107] In at least one embodiment, the present disclosure provides a vector comprising a heterologous nucleic acid encoding a pathway comprising the enzymes AAE, TKS, OAC, PT4, and a recombinant SP-CBDAS polypeptide, wherein the portion of the nucleic acid encoding the recombinant SP-CBDAS polypeptide comprises a nucleotide sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to any one of SEQ ID NOs: 43, 45, 47, 49, 93, 95, 97, 107, 109, 111, and 113. [0108] In at least one embodiment, the present disclosure provides a vector comprising a heterologous nucleic acid encoding a pathway comprising the enzymes AAE, TKS, OAC, and PT4, and a recombinant CBDAS homolog or SP-CBDAS polypeptide of the present disclosure, wherein the portion of the nucleic acid encoding the recombinant CBDAS homolog or SP- CBDAS polypeptide encodes an amino acid sequence having at least 90%, at least 95%, at 22, 24, 26, 44, 46, 48, 50, 94, 96, 98, 108, 110, 112, and 114. In at least one embodiment, the vector comprises a nucleic acid that is codon-optimized for expression in a recombinant host cell, wherein the host cell source is selected from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, Escherichia coli, or an engineered cell derived from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, Escherichia coli. [0109] In at least one embodiment, the present disclosure provides an isolated nucleic acid, wherein the nucleic acid encodes a pathway comprising the enzymes AAE, TKS, OAC, and PT4, and a recombinant SP-THCAS polypeptide of the present disclosure, wherein the portion of the nucleic acid encoding the SP-THCAS polypeptide comprises a nucleotide sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to any one of SEQ ID NOs: 121, 123, 125, 127, 129, 131, 133, and 135. In at least one embodiment, the nucleic acid encoding the pathway comprising the enzymes AAE, TKS, OAC, PT4, and a recombinant SP-THCAS polypeptide, the portion of the nucleic acid encoding the recombinant SP-THCAS polypeptide comprises a nucleotide sequence of any one of SEQ ID NOs: 121, 123, 125, 127, 129, 131, 133, and 135. [0110] In at least one embodiment, the present disclosure provides a vector comprising a heterologous nucleic acid encoding a pathway comprising the enzymes AAE, TKS, OAC, PT4, and a recombinant SP-THCAS polypeptide, wherein the portion of the nucleic acid encoding the recombinant SP-THCAS polypeptide comprises a nucleotide sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to any one of SEQ ID NOs: 121, 123, 125, 127, 129, 131, 133, and 135. [0111] In at least one embodiment, the present disclosure provides a vector comprising a heterologous nucleic acid encoding a pathway comprising the enzymes AAE, TKS, OAC, and PT4, and a recombinant SP-THCAS polypeptide of the present disclosure, wherein the portion of the nucleic acid encoding the recombinant SP-THCAS polypeptide encodes an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to any one of SEQ ID NOs: 122, 124, 126, 128, 130, 132, 134, and 136. In at least one embodiment, the vector comprises a nucleic acid that is codon-optimized for expression in a recombinant host cell, wherein the host cell source is selected from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, Escherichia coli, or an engineered cell derived from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, Escherichia coli. [0112] In at least one embodiment, the nucleic acids and vectors encoding pathway capable of producing a CBDA, THCA, and/or CBCA of the present disclosure comprise the enzymes AAE, TKS, OAC, and PT4, wherein the enzymes AAE, TKS, OAC, PT4, have the amino acid sequences of SEQ ID NO: 2 (AAE), SEQ ID NO: 4 (TKS), SEQ ID NO: 6 (OAC), and SEQ ID NO: 10 (PT4). In at least one embodiment, the nucleotide sequences encoding the pathway of cell source is selected from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, Escherichia coli, or an engineered cell derived from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, Escherichia coli. [0113] In some embodiments, the amino acid sequences of the AAE, TKS, OAC, PT4, CBDAS, and THCAS polypeptides of even-numbered SEQ ID NOs: 2-42 and the SP-CBDAS and SP- THCAS recombinant secretion peptide fusion polypeptides of even-numbered SEQ ID NOs: 44- 68 and 94-136 provided in the present disclosure include an initiating methionine (M) residue at position 1. It will be understood by the skilled artisan, however, that this initiating methionine residue may be removed by biological processing machinery, such as in a host cell or in vitro translation system, to generate a mature protein lacking the initiating methionine residue. Accordingly, it is contemplated that in any embodiment of the present disclosure comprising an amino acid sequence of an AAE, TKS, OAC, PT4, and/or CBDAS enzyme can comprise an amino acid sequence of SEQ ID NO: 2-42, 44-68, or 94-136, wherein the methionine residue at position 1 is deleted. It is also understood that nucleotides encoding the initiating methionine (M) residue at position 1 of any of the CBDAS or THCAS enzyme sequences should not be included in preparing a nucleic acid construct of SP-CBDAS or SP-THCAS for integration into a cannabinoid pathway of a recombinant host cell. [0114] Generally, the host cell source used in the recombinant host cell of the present disclosure can be any cell that can be recombinantly modified with nucleic acids and express the recombinant products of those nucleic acids, including polypeptides and metabolites produced by the activity of the recombinant polypeptides. A wide range of suitable sources of host cells are known in the art, and exemplary host cell sources useful as recombinant host cells of the present disclosure include, but are not limited to, Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, and Escherichia coli. It is also contemplated that the host cell source for a recombinant host cell of the present disclosure can include a non-naturally occurring cell source, e.g., an engineered host cell. For example, a non-naturally occurring source host cell, such as a yeast cell previously engineered for improved production of recombinant genes, may be used to prepare the recombinant host cell of the present disclosure. Accordingly, in at least one embodiment, the present disclosure provides a recombinant host cell transformed with a cannabinoid biosynthesis pathway and a heterologous nucleic acid encoding a protein that is not part of the pathway, wherein the host cell source is selected from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, Escherichia coli, or an engineered cell derived from Saccharomyces cerevisiae, Yarrowia lipolytica, Pichia pastoris, Escherichia coli. [0115] The recombinant hosts of the present disclosure comprise heterologous nucleic acids encoding a cannabinoid pathway capable of producing CBDA, THCA, and/or CBCA, wherein the heterologous nucleic acids comprise sequences encoding the recombinant SP-CBDAS or acid sequences encoding SP-CBDAS, or SP-THCAS, and the other cannabinoid pathway enzymes, are known in the art and provided herein and can readily be used in accordance with the present disclosure. Typically, the nucleic acid sequence encoding enzymes which form a part of a cannabinoid pathway, further include one or more additional nucleic acid sequences, for example, a nucleic acid sequence controlling expression of the proteins which form a part of a cannabinoid biosynthetic enzyme pathway, and these one or more additional nucleic acid sequences together with the nucleic acid sequence encoding a protein which form a part of an cannabinoid biosynthetic enzyme pathway can be considered a heterologous nucleic acid sequence. A variety of techniques and methodologies are available and well known in the art for introducing heterologous nucleic acid sequences, such as nucleic acid sequences encoding the SP-CBDAS or SP-THCAS, into a host cell so as to attain expression of the corresponding enzymes in a cannabinoid pathway. Such techniques are well known to the skilled artisan and can, for example, be found in Sambrook et al., Molecular Cloning, a Laboratory Manual, Cold Spring Harbor Laboratory Press, 2012, Fourth Ed. [0116] One of ordinary skill will recognize that the heterologous nucleic acids encoding the the SP-CBDAS or SP-THCAS polypeptides(and other pathway enzymes) will further comprise transcriptional promoters capable of controlling expression of the enzymes in the recombinant host cell. Generally, the transcriptional promoters are selected to be compatible with the host cell, so that promoters obtained from bacterial cells are used when a bacterial host cell is selected in accordance herewith, while a fungal promoter is used when a fungal host cell is selected, a plant promoter is used when a plant cell is selected, and so on. Promoters useful in the recombinant host cells of the present disclosure may be constitutive or inducible, provided such promoters are operable in the host cells. Promoters that may be used to control expression in fungal host cells such as Saccharomyces cerevisiae are well known in the art and include, but are not limited to: inducible promoters, such as a GAL1 promoter or GAL10 promoter, a constitutive promoter, such as an alcohol dehydrogenase (ADH) promoter, a glyceraldehyde-3-phosphate dehydrogenase (GPD) promoter, or an S. pombe Nmt, or ADH promoter. Exemplary promoters that may be used to control expression in bacterial cells can include the Escherichia coli promoters lac, tac, trc, trp or the T7 promoter. Exemplary promoters that may be used to control expression in plant cells include, for example, a Cauliflower Mosaic Virus 35S promoter (Odell et al. (1985) Nature 313:810-812), a ubiquitin promoter (U.S. Pat. No.5,510,474; Christensen et al. (1989)), or a rice actin promoter (McElroy et al. (1990) Plant Cell 2:163-171). Exemplary promoters that can be used in mammalian cells include, a viral promoter such as an SV40 promoter or a metallothionine promoter. All of these host cell promoters are well known by and readily available to one of ordinary skill in the art. Further nucleic acid control elements useful for controlling expression in a recombinant host cell can include transcriptional terminators, enhancers and the like, all of which may be used with disclosure. [0117] A wide variety of techniques are well known in the art for linking transcriptional promoters and other control elements to heterologous nucleic acid sequences encoding pathway genes. Such techniques are described in e.g., Sambrook et al., Molecular Cloning, a Laboratory Manual, Cold Spring Harbor Laboratory Press, 2012, Fourth Ed. [0118] Accordingly, in at least one embodiment, the heterologous nucleic acid sequences of the present disclosure comprise a promoter capable of controlling expression in a host cell, wherein the promoter is linked to a nucleic acid sequence encoding an SP-CBDAS or SP- THCAS polypeptide, and, as necessary, other enzymes constituting a cannabinoid pathway (e.g., AAE, TKS, OAC, PT4). This heterologous nucleic acid sequence can be integrated into a recombinant expression vector which ensures good expression in the desired host cell, wherein the expression vector is suitable for expression in a host cell, meaning that the recombinant expression vector comprises the heterologous nucleic acid sequence linked to any genetic elements required to achieve expression in the host cell. Genetic elements that may be included in the expression vector in this regard include a transcriptional termination region, one or more nucleic acid sequences encoding marker genes, one or more origins of replication, and the like. In some embodiments, the expression vector further comprises genetic elements required for the integration of the vector or a portion thereof in the host cell's genome. [0119] It is also contemplated that in some embodiments an expression vector comprising a heterologous nucleic acid of the present disclosure may further contain a marker gene. Marker genes useful in accordance with the present disclosure include any genes that allow the distinction of transformed cells from non-transformed cells, including all selectable and screenable marker genes. A marker gene may be a resistance marker such as an antibiotic resistance marker against, for example, kanamycin or ampicillin. Screenable markers that may be employed to identify transformants through visual inspection include β-glucuronidase (GUS) (U.S. Pat. Nos.5,268,463 and 5,599,670) and green fluorescent protein (GFP) (Niedz et al., 1995, Plant Cell Rep., 14: 403). [0120] Use of Recombinant Host Cells in Preparation of Cannabinoids [0121] As described elsewhere herein, the present disclosure provides recombinant host cells capable of producing CBDA, THCA, and/or CBCA, wherein the host cell comprises a pathway of at least the enzymes AAE, TKS, OAC, and PT4, which produce the cannabinoid, CBGA, and a recombinant SP-CBDAS or SP-THCAS capable of converting the CBGA to CBDA, THCA, and/or CBCA. In at least one embodiment of such a recombinant host cell, the recombinant SP-CBDAS or SP-THCAS polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to any one of SEQ ID NOs: 44, 46, 94, 96, 98, 108, 110, 112, 114, 116, 118, 126, 128, 130, 132, 134, and with a titer that is increased relative to a control recombinant host cell comprising the same pathway but with the SP-CBDAS of SEQ ID NO: 44, or the SP-THCAS of SEQ ID NO: 122. Accordingly, the recombinant host cell of the present disclosure can be used for improved biosynthetic production of CBDA or THCA. It is also contemplated that such a recombinant host cell can be used for the enhanced production of other rare cannabinoid compounds that are structural analogs to CBDA or THCA, including, but not limited to, the exemplary rare CBDA and THCA analog compounds provided in Table 2. [0122] In at least one embodiment, the present disclosure provides a method for producing a rare CBDA analog or a rare THCA analog comprising: (a) culturing in a suitable medium a recombinant host cell of the present disclosure; and (b) recovering the produced rare CBDA analog or THCA analog. [0123] In at least one embodiment, a recombinant host cell of the present disclosure can be used to produce a rare CBDA analog or THCA analog that is a varin series cannabinoid selected from cannabidivarinic acid (CBDVA), cannabidivarin (CBDV), Δ 9 - tetrahydrocannabivarinic acid (THCVA), Δ 9 -tetrahydrocannabivarin (THCV), cannabichromevarinic acid (CBCVA), cannabichromevarin (CBCV), cannabigerovarinic acid (CBGVA), cannabigerovarin (CBGV), and any combination thereof. However, it is also contemplated that the recombinant host cells of the present disclosure can be used to produce other CBDA analog or THCA analog compounds of Table 2 that do not include a varin group, including any of the cannabinoids selected from Δ 8 -tetrahydrocannabinolic acid (Δ 8 -THCA), Δ 8 - tetrahydrocannabinol (Δ 8 -THC), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabinolic acid (CBNA), cannabinol (CBN), cannabidibutolic acid (CBDBA), cannabidibutol (CBDB), Δ 9 -tetrahydrocannabutolic acid (Δ 9 -THCBA), Δ 9 -tetrahydrocannabutol (Δ 9 -THCB), cannabidiphorolic acid (CBDPA), cannabidiphorol (CBDP), Δ 9 -tetrahydrocannabiphorolic acid (Δ 9 -THCPA), Δ 9 -tetrahydrocannabiphorol (Δ 9 -THCP), cannabicyclolic acid (CBLA), cannabicyclol (CBL), cannabielsoinic acid (CBEA), cannabielsoin (CBE), cannabicitranic acid (CBTA), cannabicitran (CBT), and any combination thereof. [0124] It is also contemplated that the method for producing CBDA of the present disclosure can further comprise contacting a cell-free extract of the culture containing the produced cannabinoid, CBGA or CBGVA, with CBDAS homolog polypeptide of the present disclosure, such as CBDAS_Var95 (SEQ ID NO: 20), as a biocatalytic reagent. In such an embodiment of the method, the biocatalytic reagent used is an isolated CBDAS enzyme capable of converting the produced cannabinoid, CBGA or CBGVA, to a different cannabinoid compound, CBDA or CBDVA. [0125] In another embodiment of such a method using a cell-free extract, a chemical reagent is contacted with the culture, wherein the reagent is capable of chemically modifying the produced cannabinoid, e.g., CBDA, can be used to produce a derivative compound of the cannabinoid, comprising a nucleic acid encoding a recombinant SP-CBDAS polypeptide of the present disclosure, which provide improved CBDA production in terms of titer, yield, and production rate can be used in the production of a downstream CBDA analog or derivative (e.g., CBD or other compounds of Table 2) by contacting the cell-free extract of the culture medium containing CBDA with a chemical reagent. Such derivative compounds of CBDA can include a wide range of naturally-occurring and non-naturally occurring compounds. [0126] For example, cannabinoid derivative compounds produced using the recombinant host cells and methods of the present disclosure can include any compound structurally related to a cannabinoid compound (e.g., compounds of Table 2) but which lacks one or more of the chemical moieties present in the cannabinoid compound from which it derives. Exemplary chemical moieties that may be lacking in a cannabinoid derivative include, but are not limited to, methyl, alkyl, alkenyl, methoxy, alkoxy, acetyl, carboxyl, carbonyl, oxo, ester, hydroxyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, heterocyclylalkenyl, heteroarylalkenyl, arylalkenyl, heterocyclyl, aralkyl, cycloalkylalkyl, heterocyclylalkyl, heteroarylalkyl, and the like. [0127] Alternatively, cannabinoid derivative compounds using the recombinant host cells and methods of the present disclosure can include one or more additional chemical moieties that are not present in the cannabinoid compound from which it derives. Exemplary chemical moieties that may be added in a cannabinoid derivative include, but are not limited to azido, halo (e.g., chloride, bromide, iodide, fluorine), methyl, alkyl, alkynyl, alkenyl, methoxy, alkoxy, acetyl, amino, carboxyl, carbonyl, oxo, ester, hydroxyl, thio, cyano, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, heterocyclylalkenyl, heterocyclylalkynyl, heteroarylalkenyl, heteroarylalkynyl, arylalkenyl, arylalkynyl, spirocyclyl, heterospirocyclyl, heterocyclyl, thioalkyl, sulfone, sulfonyl, sulfoxide, amino, alkylamino, dialkylamino, arylamino, alkylarylamino, diarylamino, N-oxide, imide, enamine, imine, oxime, hydrazone, nitrile, aralkyl, cycloalkylalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, nitro, thioxo, and the like. [0128] Accordingly, in at least one embodiment, the present disclosure provides a method of producing a derivative compound of a cannabinoid precursor or cannabinoid, wherein the method comprises: (a) culturing in a suitable medium a recombinant host cell of the present disclosure; and (b) recovering the produced derivative compound. In at least one embodiment, the method of producing a derivative compound of a cannabinoid precursor or cannabinoid can further contacting a cell-free extract of the culture of the recombinant host cell containing the produced cannabinoid precursor or cannabinoid with a biocatalytic reagent or chemical reagent capable of converting the cannabinoid precursor or cannabinoid to a derivative compound. [0129] Derivative compounds of cannabinoid precursor and cannabinoid compounds that can be produced with improved yield using a recombinant host cell of the present disclosure can properties of pharmaceutical metabolism and/or pharmacokinetics (e.g. solubility, bioavailability, absorption, distribution, plasma half-life and metabolic clearance). Modifications typically providing such improved pharmaceutical properties can include, but are not limited to, halogenation, acetylation and methylation. It is also contemplated that the derivative compounds of cannabinoids produced by the methods disclosed herein can include pharmaceutically acceptable isotopically labeled compounds. For example, a cannabinoid compound wherein the hydrogen atoms are replaced or substituted by one or more deuterium or tritium atoms. Such isotopically labeled derivatives of cannabinoids can be useful in studies of in vivo pharmacokinetics and tissue distribution. [0130] Upon production by the host cells or in the cell-free mixture of the rare cannabinoid precursors or rare cannabinoid compounds in accordance with the compositions, host cells, and methods of the present disclosure, the desired compounds may be recovered from the host cell suspension or cell-free mixture and separated from other constituents, such as media constituents, cellular debris, etc. Techniques for separation and recovery of the desired compounds are known to those of skill in the art and can include, for example, solvent extraction (e.g. butane, chloroform, ethanol), column chromatography-based techniques, high- performance liquid chromatography (HPLC), for example, and/or countercurrent separation (CCS) based systems. The recovered rare cannabinoid compounds may be obtained in a more or less pure form, for example, the desired rare cannabinoid compound of purity of at least about 60% (w/v), about 70% (w/v), about 80% (w/v), about 90% (w/v), about 95% (w/v) or about 99% (w/v). [0131] It also is contemplated that the cannabinoid, cannabinoid precursor, cannabinoid precursor derivative, or cannabinoid derivative recovered using the methods of the present disclosure can be in the form of a salt. In at least one embodiment, the recovered salt of the cannabinoid, cannabinoid precursor, cannabinoid precursor derivative, or cannabinoid derivative is a pharmaceutically acceptable salt. Such pharmaceutically acceptable salts retain the biological effectiveness and properties of the free base compound. [0132] As described elsewhere herein, the rare cannabinoid compounds provided by the recombinant host cells and methods of the present disclosure are contemplated to have exhibit biological and pharmacological properties like those of the more well-studied cannabinoids such as THC and CBD. Accordingly, in at least one embodiment, the present disclosure also provides a composition comprising a rare cannabinoid, such as a varin cannabinoid, prepared using the recombinant host cells and methods disclosed herein. It is contemplated that the rare cannabinoid compositions provided by the recombinant host cells and methods of the present disclosure can include pharmaceutical compositions, food compositions, and beverage compositions, containing a rare cannabinoid. Generally, compositions comprising rare cannabinoid compounds can further comprise any of the well-known vehicles, excipients and like, used in the art of formulating pharmaceutical, food, or beverage compositions. For example, pharmaceutical compositions can contain any of the typical pharmaceutically acceptable excipients including, but are not limited to, liquids such as water, saline, polyethylene glycol, hyaluronic acid, glycerol and ethanol. Pharmaceutically acceptable salts can also be included therein, for example, mineral acid salts such as hydrochlorides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, benzoates, and the like. In at least one embodiment, a pharmaceutical composition can comprise a pharmaceutically acceptable excipient that serves as a stabilizer of the rare cannabinoid composition. Examples of suitable excipients that also act as stabilizers include, without limitation, pharmaceutical grades of dextrose, sucrose, lactose, sorbitol, inositol, dextran, and the like. Other suitable pharmaceutical excipients can include, without limitation, starch, cellulose, sodium or calcium phosphates, citric acid, glycine, polyethylene glycols (PEGs), and combinations thereof. EXAMPLES [0133] Various features and embodiments of the disclosure are illustrated in the following representative examples, which are intended to be illustrative, and not limiting. Those skilled in the art will readily appreciate that the specific examples are only illustrative of the invention as described more fully in the claims which follow thereafter. Every embodiment and feature described in the application should be understood to be interchangeable and combinable with every embodiment contained within. Example 1: Biosynthesis of the cannabinoids, CBDA, THCA, and/or CBCA, from HA or OA by engineered Saccharomyces cerevisiae [0134] This example illustrates a study showing that Saccharomyces cerevisiae strains derived from CEN.PK2-1D with a pathway capable of converting hexanoic acid (HA) or the olivetolic acid (OA) to the cannabinoid, CBGA, can be further engineered to incorporate CBDA synthase (CBDAS) homologs and variants. Some of the resulting engineered strains when cultured in the presence of HA (or the cannabinoid precursor, OA) are capable of converting the CBGA to the further downstream cannabinoids, CBDA, THCA, and/or CBCA. [0135] Materials and Methods [0136] A. Identification of candidate CBDAS homologs [0137] Public and internal cannabis genomes were searched for proteins >50% identical to THCAS-like synthases. Unique hits were aligned and clustered. 12 potential CBDAS homologs were selected from the cluster tree for further screening. [0138] B. CBDAS library construction [0139] Sequences encoding the “wild-type” d28_CBDAS and the 12 potential CBDAS homolog polypeptides with a N-terminal SP-Alpha secretion peptide of SEQ ID NOs: 44, 46, 48, 50, 52, sequences of SEQ ID NOs: 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, and 67. The yeast codon optimized polynucleotide sequences encoding the fused SP-Alpha_CBDAS polypeptides were synthesized (Twist Bioscience Corporation, South San Francisco, CA, USA). The optimized polynucleotide of SEQ ID NO: 43 encoding SP-Alpha_d28_CBDAS (SEQ ID NO: 44) was subcloned using NEBuilder® HiFi DNA Assembly Master Mix (NEB) with the Gal1 promoter into an E. coli construct containing the ALD4 terminator along with homology regions to the X-3 integration site (EasyClone 2.0) needed for integration into the yeast genome to generate wbPlasmid089 shown in FIG.7. Linear DNA for integration for the Alpha_d28_CBDAS control was PCR amplified from wbPlasmid089. Linear DNA for integration of all other synthesized homologs were assembled by SOE-PCR to contain the Gal1 promoter, ALD4 terminator, and X-3 homology regions for integration. Primers used to assemble the linear DNA for integration are provided in Table 4 below [0140] TABLE 4 SEQ ID Name Sequence NO: [0141] C. Expression of SP-Alpha-CBDAS homolog library in yeast [0142] The linear donor DNA for each SP-Alpha-CBDAS homolog was pooled and transformed for integration into the X-3 site of two Saccharomyces cerevisiae strains using CRISPR-Cas9: (1) a strain incorporating only the 82 aa truncated PT4 prenyltransferase, d82_PT4 (SEQ ID NO: 10); or (2) a strain incorporating the cannabinoid biosynthesis pathway including genes encoding the enzymes C. sativa AAE1 (SEQ ID NO: 2), TKS (SEQ ID NO: 4), OAC (SEQ ID NO: 6), and d82_PT4 (SEQ ID NO: 10). Linear donor DNA for the SP-Alpha_d28_CBDAS reference construct was transformed separately. Colonies from the SP-Alpha_CBDAS homolog library and SP-Alpha_d28_CBDAS control build were picked for screening. [0143] D. Screening of CBDAS homolog library for cannabinoid biosynthesis [0144] Yeast strains were grown in 0.3 mL YPD media for 24 hr at 30°C. The parent strain to each integration was used a baseline control. Cultures were then sub-cultured into 0.3 mL YPD media with feeding of OA for the strains containing only PT and feeding of HA for the strains containing the four enzyme cannabinoid biosynthesis pathway of enzymes, AAE1 (SEQ ID NO: 2), TKS (SEQ ID NO: 4), OAC (SEQ ID NO: 6), and PT4 (SEQ ID NO: 10). OA or HA were fed to a final concentration of 1 mM and the cultures grown for 72 hours at 30°C. [0145] Samples for LC/MS analysis were prepared by extracting whole broth of the culture and diluting with acetonitrile. The prepared samples were loaded onto Agilent LC/MS (1290 Infinity II LC system with 6470B Triple quadrupole mass spectrometry) for analysis. The UPLC solid phase was a C18 column, and the mobile phase was the Acetonitrile/Water system. [0146] THCA was identified with primary mass transition 357.2/313.2 and secondary transition 357.2/245.1; CBCA was identified with primary mass transition 357.2/313.2 and secondary transition 357.2/339.1. CBDA was identified with primary mass transition 357.2/339.1 and secondary transition 357.2/245.1, The peak identities are also confirmed by their LC/MS retention time. The concentrations of THCA, CBCA, and CBDA were quantified by referring to a standard curve. The top CBDAS homologs showing activity were confirmed by LC/MS. [0147] The library clones from the pooled screening showing detectable activity were sequenced to identify the integrated SP-Alpha-CBDAS homolog showing activity. [0148] Results: As shown by the results summarized in Table 5 (below), the pooled screening followed by hit sequencing identified three SP-Alpha CBDAS homolog polypeptides producing detectable levels of the downstream cannabinoids, CBDA, THCA, and/or CBCA: SP- Alpha_CBDAS_Var95 (SEQ ID NO: 46), SP-Alpha_Cs10_4 (SEQ ID NO: 46) and SP- Alpha_CBDAS2 (SEQ ID NO: 48). Only the engineered yeast strains expressing the homolog, CBDAS_Var95 produced all three cannabinoids, CBDA, THCA, and CBCA when fed either OA, in the case of the strain only incorporating a heterologous PT4 enzyme, or HA, in the case of the strain incorporating the complement of four heterologous cannabinoid pathway enzymes, AAE1, TKS, OAC, and PT4. The other nine SP-Alpha-CBDAS homologs tested not showing up expression, or simply not enough screening of the pool in this study. [0149] TABLE 5 AA Sequence SP-CBDAS (SEQ ID NO: ) CBDA THCA CBCA Example 2: Secretion peptide screening for enhanced cannabinoid biosynthesis by recombinant CBDAS and THCAS in Saccharomyces cerevisiae [0150] Efficient secretion of the cannabinoid synthases, CBDAS and THCAS in the trichome cells of the plant C. sativa is believed to be necessary to facilitate efficient production of the cannabinoids, CBDA, THCA, and/or CBCA. This example illustrates a study that screens a library of various secretion peptides in combination with CBDAS and THCAS for the ability to enhance cannabinoid production of CBDA and THCA when the cannabinoid synthases are expressed in yeast strains engineered with a cannabinoid pathway that produces CBGA. [0151] Materials and Methods [0152] A. Secretion peptide library construction [0153] The secretion peptides from various source organisms selected for library construction and screening are summarized below in Table 6. [0154] TABLE 6 SP Name SEQ ID NO: SEQ ID NO: Abbrev. (source organism) (nt) (aa) (S. cerevisiae) ucleotide pools (Opools, Integrated DNA Technologies, San Diego, CA, USA) with a 5’ flanking region to the Gal1 promoter and a 3’ flanking region to the yeast optimized polynucleotide encoding d28_CBDAS (SEQ ID NO: 14) and d28_THCAS (SEQ ID NO: 18). Each synthase was PCR amplified with their respective oligo pools then subcloned using NEBuilder® HiFi DNA Assembly Master Mix (NEB) into an E. coli construct containing the Gal1 promoter and ALD4 terminator cassette along with homology regions needed for integration into the X-3 site (EasyClone 2.0) of the yeast genome. E. coli colonies from the cloning transformation for each synthase were pooled and plasmid DNA was isolated from the pools. Linear donor DNA was amplified from the plasmid DNA pools and used to transform yeast. The N-terminal SP-Alpha constructs were built separately from the pool and used as a reference control for both CBDAS and THCAS. Oligo pools and primers used to assemble the linear donor DNA for integration are provided in Table 7 below. [0156] TABLE 7 SEQ ID Name Sequence NO: GGGTGTATCTTTAGAGAAGAGAGAAGCTGAAGCCAATCCTAGAGAA GTTTGGAGAAGAGGGAAGCAGAGGCTAACCCAAGGGAGAACTTCCT p p g _ _ secretion peptide libraries (SP_AA, SP_AT, SP_IV, and SP_KP) were fused to CBDAS_Var95. Linear DNA for these four SP-CBDAS_Var95 fusions were constructed using SOE-PCR to contain the Gal1 promoter, appropriate secretion peptide, ALD4 terminator, and X-3 homology regions for integration. For a list of primers see Table 7. [0158] B. Transformation and expression of secretion peptide library in yeast [0159] The pooled SP library linear donor DNA for d28_CBDAS and d28_THCAS were transformed for integration into the X-3 site of various Saccharomyces cerevisiae strains using CRISPR-Cas9. All Saccharomyces cerevisiae strains transformed had the pathway of cannabinoid biosynthesis, which included the following genes from Cannabis sativa: AAE1 (SEQ ID NO: 2), TKS (SEQ ID NO: 4), OAC (SEQ ID NO: 6), and PT4 (SEQ ID NO: 10). builds were picked for screening. Linear DNA for each of the four SP-CBDAS_Var95 fusions were transformed separately for integration into the X-3 site of a HA-fed Saccharomyces cerevisiae strain using CRISPR-Cas9. The SP-Alpha_CBDAS_Var95 fusion was used as a reference control for the four tested SP-CBDAS_Var95 fusions. Colonies from each SP- CBDAS_Var95 fusion were picked for screening. [0160] C. Screening secretion peptide library for cannabinoid biosynthesis [0161] Yeast strains were grown in 0.3 mL YPD media for 24 hr at 30°C. The parent strain to each integration was used a baseline control. Cultures were then sub-cultured into 0.3 mL YPD media with feeding of HA to 1 mM final concentration and grown for 72 hours at 30°C. The whole broth of the culture was extracted and diluted with acetonitrile for sample preparation. The prepared samples were loaded onto Agilent LC/MS (1290 Infinity II LC system with 6470B Triple quadrupole mass spectrometry) for analysis. The UPLC solid phase was using C18 column, and the mobile phase was using the Acetonitrile/Water system. THCA was identified with primary mass transition 357.2/313.2 and secondary transition 357.2/245.1; CBCA was identified with primary mass transition 357.2/313.2 and secondary transition 357.2/339.1; CBDA was identified with primary mass transition 357.2/339.1 and secondary transition 357.2/245.1; Their identities are also confirmed by their LC/MS retention time. The concentrations of THCA, CBCA, and CBDA were quantified by referring to a standard curve. Top variants showing activity were confirmed by LC-MS. [0162] D. Sequence identification [0163] Secretion peptide sequences from selected top library clones showing activity from both the SP-d28_CBDAS and SP-d28_THCAS libraries were identified by PCR and sequencing. [0164] Results: [0165] The combinations of secretion peptides fused with either THCAS, CBDAS, or CBDAS_Var95 that resulted in production of THCA, CBDA, and CBDA, respectively, are summarized in Table 8 below. [0166] TABLE 8 SEQ ID SEQ ID NO: NO: SP KP CBDAS Var95 ++ 111 112 ited 3-fold to 4- fold increased levels of THCA or CBDA production, respectively, relative to the control SP- Alpha secretion peptide, fused with the same enzymes. The secretion peptide SP-KP when fused with CBDAS resulted in engineered yeast exhibiting 3-fold to 4-fold increased levels of CBDA production relative to the control secretion peptide, SP-Alpha fused with CBDAS. The combination of the SP_IV and SP_KP secretion peptides when fused with the CBDAS homolog, CBDAS_Var95, exhibited 2-fold to 3-fold increased levels of CBDA production relative to the control secretion peptide, SP-Alpha fused with CBDAS_Var95. [0168] While the foregoing disclosure of the present invention has been described in some detail by way of example and illustration for purposes of clarity and understanding, this disclosure including the examples, descriptions, and embodiments described herein are for illustrative purposes, are intended to be exemplary, and should not be construed as limiting the present disclosure. It will be clear to one skilled in the art that various modifications or changes to the examples, descriptions, and embodiments described herein can be made and are to be included within the spirit and purview of this disclosure and the appended claims. Further, one of skill in the art will recognize a number of equivalent methods and procedure to those described herein. All such equivalents are to be understood to be within the scope of the present disclosure and are covered by the appended claims. [0169] Additional embodiments of the invention are set forth in the following claims. [0170] The disclosures of all publications, patent applications, patents, or other documents mentioned herein are expressly incorporated by reference in their entirety for all purposes to the same extent as if each such individual publication, patent, patent application or other document were individually specifically indicated to be incorporated by reference herein in its entirety for all purposes and were set forth in its entirety herein. In case of conflict, the present specification, including specified terms, will control.