Sequence record
NCBI
Sequence records identify nucleotide or protein material and its version. Gene, locus, and variants must be checked in the corresponding genomic records; a protein sequence alone does not contain all of this information.
How to interpret THCA synthase on this page
The THCAS gene encodes THCA synthase in Cannabis sativa. The enzyme converts CBGA into THCA. The biochemical reaction, the deposited experimental structure, and computational interpretations are presented as distinct evidence layers.
Follow the reasoning in this order: confirm identity and reaction; inspect the structure, cofactor, and residues; then evaluate hypotheses, provenance, and limitations. The glossary defines the essential terms used along this path.
PAGE GLOSSARY
Essential terms for interpreting THCA synthase
These definitions explain how each term is used on this page. They support reading but do not replace the cited records and articles.
Open the contextual glossary Gene · enzyme · reaction · structure · modeling
- THCAS
- Gene that encodes THCA synthase. The gene name should not be used as a synonym for the protein.
- THCA synthase
- FAD-dependent enzyme that catalyzes the oxidative conversion of CBGA into THCA.
- CBGA
- Cannabigerolic acid, a substrate of THCA synthase and a precursor of several cannabinoids. Its deprotonated form is cannabigerolate, used in the enzyme equation on this page.
- THCA
- Tetrahydrocannabinolic acid formed by the enzyme. It can lose CO₂ to form THC; THCA and THC are not the same molecule.
- FAD
- Flavin adenine dinucleotide, a protein-bound cofactor that participates in the oxidation reaction.
- Cofactor
- A non-protein component required for or supporting enzyme activity. FAD is the primary example on this page.
- PDB 3VTE
- Identifier of the experimental THCA-synthase model deposited in the Protein Data Bank.
- Crystallography
- Method that uses X-ray diffraction to derive a three-dimensional model from a protein crystal.
- Ångström (Å)
- A unit equal to 10⁻¹⁰ metre, used to report structural resolution and molecular distances.
- Residue
- An amino acid at a defined position in the protein chain, such as Cys176 or Tyr484.
- Active site
- Enzyme region associated with substrate recognition and catalysis. A structure alone does not prove every mechanistic step.
- Molecular docking
- Computational method that proposes interaction poses. It generates hypotheses and does not prove binding or biological activity.
- Molecular dynamics
- Simulation of atomic motion over time whose outcome depends on the model, parameters, and sampling.
- Chemotype
- Observed chemical profile of a plant. It should not be inferred definitively from a single genetic marker.
- Haplotype
- A set of nearby variants that tends to be inherited together within a genomic region.
Q&A EVIDENCE MAP
Find the source for each type of evidence
Follow these routes to assemble an answer rather than relying on a single paragraph. Each route connects molecular identity, structural observations, functional interpretation, and explicit evidence boundaries.
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01
Identity, gene, sequence, and variants
Confirm the organism, enzyme record, protein-record accession (the identifier assigned to the protein entry), construct, locus context, and reported sequence variation.
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02
Structure and functional features
Inspect the experimental record, construct, structural partitions, FAD, catalytic residues, and unresolved limits.
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03
Mechanism, cofactor, and molecular context
Relate the oxidative reaction to the proposed catalytic roles of FAD and selected residues without treating a static structure as a complete mechanism.
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04
Evidence, prediction, and uncertainty
Separate sequence annotation, experimental coordinates, predictive models, mechanistic interpretation, and hypotheses.
ENZYME FUNCTION · EC 1.21.3.7
CBGA oxidation catalyzed by THCA synthase
The structural record provides the experimental anchor for this page. Its associated protein reference is UniProt Q8GTB6, while BRENDA supplies the complementary enzyme classification and reaction record.
cannabigerolate + O2
Δ9-tetrahydrocannabinolate + H2O2
The equation follows IUBMB EC 1.21.3.7 and names the carboxylate forms. The introductory glossary uses the corresponding acid names.
- Structural anchor
- PDB 3VTE · chain A · residues 28–545
- Protein reference
- UniProt Q8GTB6
- Experimental method
- X-ray diffraction · 2.75 Å
- Cofactor
- FAD
Evidence boundary. The molecular geometry and residue interpretation on this page derive from that record. The reaction classification is complementary functional evidence and does not replace the structural record.
Source governance and traceability
The RCSB Protein Data Bank maintains the structural record used on this page. To make the analysis verifiable, cite the structural identifier shown in the record below, the original authors, and the repository; keep protein and reaction references distinct.
| Organism | Cannabis sativa L. |
|---|---|
| Protein | THCA synthase |
| Protein reference | UniProt Q8GTB6 |
| Structure | PDB 3VTE |
| Structure coverage | Chain A, UniProt residues 28–545 |
| Experimental method | X-ray diffraction, 2.75 Å resolution |
| Enzyme classification | EC 1.21.3.7 |
| Reaction | Cannabigerolate + O2 → Δ9-tetrahydrocannabinolate + H2O2 |
| Cofactor | FAD |
| Curatorial fields | Source, evidence level, review status, and notes |
| Traceability | PDB, UniProt, and BRENDA identifiers, publication record, and retrieval history |
Sequence, predicted fold, and experimental structure
Each record answers a different question: sequence identifies the protein, a predicted fold offers a model, and the experimental record provides experimentally derived coordinates under defined conditions.
Predicted model
AlphaFold
This model provides a predicted fold and local confidence estimates. It can guide structural questions but does not measure molecular flexibility or replace experimental coordinates.
Experimental structure
PDB 3VTE
This experimentally determined coordinate model reports observed geometry and cofactor placement under specific conditions. It is a primary source for structure-informed interpretation, not a complete account of function or molecular dynamics.
Structure-informed reading of THCA synthase
The experimental coordinate model lets readers inspect the cofactor, residue context, and proposed catalytic regions alongside the biochemical literature.
The enzyme catalyzes the oxidative conversion of cannabigerolic acid into tetrahydrocannabinolic acid in Cannabis sativa. The structure can support discussion of FAD chemistry, residue context, substrate access, and why static models are one part of the scientific picture.
The legend and residue ranges below are grounded in the local PDB copy and the project modeling notes. The 502-residue count refers to polymer residues modeled with coordinates, while the domain bands follow the modeling partition used for visualization.
Reading the structural record
The local 3VTE.pdb file contains 502 modeled residues, 4,211 atoms, and highlights NAG (6) and FAD (1).
Structural inspection
Regions highlighted in the visualization
Inspect FAD, anchors 114/176, ASA-loop, Ala116 (chain A), and Gly376/Ser448. Compare their positions with the annotations and cited biochemical sources.
Structural interpretation key
Modeling partitions
- Structural domain I (model partition; residues 1-290)
- Structural domain II (model partition; residues 291-545)
- FAD cofactor and catalytic activity (FAD; anchors 114/176)
- Cofactor anchors (His114/Cys176) and proposed catalytic base (Tyr484)
- Substrate-binding cavity (SBR; support residues 292/417)
- Segment 354–380 (ASA loop in the visualization)
- Ala116 in chain A (comparison position; no specific function assigned)
- Comparison positions (Gly376, Ser448)
Modeling references
Data sources
- Phytochemical and genetic analyses of ancient cannabis from Central Asia
- Resurrected Ancestral Cannabis Enzymes Unveil the Origin and Functional Evolution of Cannabinoid Synthases
- Structure and Function of Δ1-Tetrahydrocannabinolic Acid (THCA) Synthase, the Enzyme Controlling the Psychoactivity of Cannabis sativa
- Crystal Structure of Tetrahydrocannabinolic Acid Synthase from Cannabis sativa (RCSB PDB: 3VTE)
The interactive workbench below allows readers to inspect these annotations and generate a PyMOL script.
Complementary dossier: genome, evolution, and expression
The preceding sections examine the reaction and experimental structure. This dossier adds genomic organization, synthase evolution, trichome expression, marker applications, and primary references.
Open the THCA synthase technical dossier and references Genome · evolution · expression · markers · references
1. Genomic location and organization
In the genome assemblies discussed by the cited mapping studies, THCAS- and CBDAS-family loci occur in a repetitive region associated with chemotype. Historically, THCA and CBDA production was interpreted through a simple Mendelian B-locus model, with BT for THC and BD for CBD. Current genomic models add copy-number variation, haplotype structure, transposable elements, and assembly-specific coordinates. Locus size, chromosome placement, and recombination estimates should therefore be reported with the cultivar and reference assembly.
2. Evolutionary history of cannabinoid synthases
Cannabinoid synthases belong to the berberine bridge enzyme-like family. Villard et al. (2026) inferred ancestral sequences and tested enzymes produced from them. Reconstructed ancestral enzymes showed catalytic promiscuity: they converted CBGA into more than one product — THCA, CBDA, and CBCA — in vitro. These assays support hypotheses about ancestral function; they did not test an enzyme recovered from ancient plant remains. The study relates later specialization to gene duplication and diversification. Archaeobotanical and phytochemical evidence from ancient plant remains can inform the history of human use, but it does not by itself identify modern THCAS alleles or establish an ancestral enzyme function.
3. Expression in glandular trichomes
Expression studies cited for this module report THCAS enrichment in secretory disk cells of glandular trichome heads, especially in female inflorescences. The following findings come from distinct regulatory studies and should not be treated as one experimentally validated circuit:
- CsYABBY3 and CsAS1 form a positive feedback loop that supports cannabinoid biosynthesis and trichome differentiation. Zhu et al. (2026) examined activation of the CsPT4 and CsCBDAS promoters.
- CsAP2L1 promotes THCAS-promoter activity in the assays reported by Liu et al. (2021).
- CsMYB1 and CsWRKY1 were proposed as negative regulators of THCAS expression in that study; this does not establish repression of the entire pathway in every context.
4. Applications and limits of breeding markers
Distinguishing potentially functional and nonfunctional THCAS copies can support breeding and jurisdiction-specific compliance workflows. Methods such as RFLP and high-resolution melting analysis (HRM) use selected polymorphisms to estimate chemotype during the vegetative stage. These markers are predictive rather than definitive and should be interpreted with copy number, haplotype, cultivar, growth conditions, and measured cannabinoid profiles.
5. References consulted
Each reference below links to its verified DOI or original publisher record. Titles are presented in full so visitors can identify the evidence before opening the source.
- Shoyama et al. (2012) — Structure and function of Δ1-tetrahydrocannabinolic acid (THCA) synthase, the enzyme controlling the psychoactivity of Cannabis sativa
- Russo et al. (2008) — Phytochemical and genetic analyses of ancient cannabis from Central Asia
- Villard et al. (2026) — Resurrected ancestral cannabis enzymes unveil the origin and functional evolution of cannabinoid synthases
- Zhu et al. (2026) — A novel CsYABBY3–CsAS1 feedback loop coordinates trichome differentiation and cannabinoid biosynthesis in Cannabis sativa L.
- Lynch et al. (2025) — Domesticated cannabinoid synthases amid a wild mosaic cannabis pangenome
- Allen et al. (2026) — The structure of the chemotype determining locus in Cannabis sativa
- Cirovic et al. (2017) — Differentiation of Cannabis subspecies by THCA synthase gene analysis using RFLP
- Kojoma et al. (2006) — DNA polymorphisms in the tetrahydrocannabinolic acid (THCA) synthase gene in “drug-type” and “fiber-type” Cannabis sativa L.
- Sirikantaramas et al. (2005) — Tetrahydrocannabinolic acid synthase, the enzyme controlling marijuana psychoactivity, is secreted into the storage cavity of the glandular trichomes
- Sirangelo, Ludlow, and Spadafora (2022) — Multi-omics approaches to study molecular mechanisms in Cannabis sativa
- Gloerfelt-Tarp et al. (2023) — Using a global diversity panel of Cannabis sativa L. to develop a near infrared-based chemometric application for cannabinoid quantification
- de Meijer et al. (2003) — The inheritance of chemical phenotype in Cannabis sativa L.
Molecular visualization and structural annotations
The interactive workspace combines the experimental record, residue annotations, and a PyMOL script generator. Each annotation separates what is observed in the model from biochemical interpretation.
Visualization locates residues and the cofactor but does not measure enzyme activity. Consult the cited experiments when interpreting each position.
Interactive workstation
PyMOL Script Generator
Use the reference structure as a transparent starting point for molecular inspection. Select the features to emphasize, generate a reproducible PyMOL script, and carry the result into a documented curation workflow.
- Use the reference: the project supplies the experimental structure file.
- Define the view: set colors and select the structural annotations.
- Generate and export: update the script, then download the
.pmlfile for PyMOL. - Read the structure: activate the 3D view or select a curated residue.
Generated script
Interactive molecular inspection
Locate residues and review the evidence
Select a curated residue or click an atom. The explorer locates the selection, separates structural observation from functional interpretation, and reports the supporting source.
Structure appearance
Structure colors
Choose the colors. The 3D view and PyMOL script update without reloading the structure.
Colors will be applied when the 3D view is activated.
3D viewer ready on demand
PNG: 2400 × 1800 px.
Source, citation, and rights for the exported image: structural data from PDB 3VTE (DOI 10.2210/pdb3VTE/pdb), made available by wwPDB under CC0 1.0. Structural interpretation based on Shoyama et al. (2012). Visual composition © 2026 Kannabium. The PNG includes the source, article, license, colors, and active selection.
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Drag to rotate, scroll to zoom, and click an atom to inspect its residue. The spatial label follows the selected residue.
His114 and Cys176 have covalent links to FAD recorded in 3VTE; Tyr484 has a proposed catalytic role. Gly376 and Ser448 are comparison positions with no catalytic role assigned on this page.
Viewer summary
Status
Initializing...
Manual fallback template (optional)
Use this minimal template for manual work without a connection. To reproduce the selections made on this page, download the script from the generator above.
Show minimal PyMOL fallback template
load 3VTE.pdb
hide everything
show cartoon, polymer.protein
color forest, polymer.protein
select fad, resn FAD
show sticks, fad
color yellow, fad
zoomGuided analytical activities
- Structure inspection - load the THCA synthase structure and identify the protein chain, cofactors, secondary structures, and visible ligands.
- Pathway connection - relate CBGA, THCA, and THC, and explain why enzyme structure matters for understanding cannabinoid biosynthesis.
- Curatorial note - write a short note linking the structure to a source, domain, entities, and evidence level.
- PyMOL scripting - generate a script that highlights the protein, cofactor, and selected residues.
- Database modeling - propose tables for species, genes, proteins, compounds, structures, sources, and curatorial notes.
- Critical evaluation - discuss what a crystal structure can show and what it cannot prove by itself.
Scope of inference from an experimental structure
The structure is an experimental model, but its interpretation remains bounded by resolution, sample preparation, and the evidence available for function.
- A crystal structure is a model derived from experimental data.
- It may represent one conformational state.
- It does not automatically explain full enzymatic dynamics.
- Docking and molecular simulations generate hypotheses, not final biological proof.
- Functional claims require biochemical, genetic, and experimental evidence in addition to structural analysis.
Document model quality, parameters, sampling, and data provenance; interpret results alongside literature, sequence analysis, enzymology, and pathway data.
CONCLUSION
What is established and what remains under evaluation
Established
THCAS encodes an enzyme that converts CBGA into THCA, and the Protein Data Bank contains an experimental structural model of that protein.
Requires additional evidence
Mechanistic steps, variant effects, and functional consequences require biochemical, genetic, or cellular data.
Next verifiable step
Compare residues and hypotheses with the cited studies, recording the source, method, and limit of each conclusion.
In the wider reading path, THCA synthase supplies the plant-side enzymatic step that connects Cannabis sativa to THCA biosynthesis. The separate CB1R module adds a vertebrate pharmacological context; it is not part of the plant biosynthetic pathway and does not imply direct cross-kingdom coevolution.
Its value as a teaching case lies in reading a plant enzyme through its sequence, structure, biochemical evidence, and unresolved questions.
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REUSING AN ANALYSIS
Data and criteria for downstream analysis
Identify the enzyme
Record Cannabis sativa, the protein-record accession UniProt Q8GTB6, and the PDB structure 3VTE. Identify the construct and chain used in the analysis.
Record the analysis parameters
Record the PDB version, selected residues, cofactor, annotation source, and visualization or analysis parameters. Save the generated PyMOL script with these records.
Support the functional interpretation
Distinguish the coordinates and bonds observed in 3VTE from proposed catalytic roles. Cite the biochemical assay or comparative study that supports each claim about enzyme function or evolution.