Cystathionine beta-synthase (CBS) is a PLP- and heme-containing enzyme (EC 4.2.1.22) that catalyzes the first and rate-limiting step of the transsulfuration pathway, condensing L-serine with L-homocysteine to form cystathionine. CBS is unique among PLP-dependent enzymes in also binding a b-type heme cofactor that functions as a redox sensor. The enzyme is allosterically activated by S-adenosyl-L-methionine (SAM) binding to its C-terminal regulatory domain containing tandem CBS (Bateman) motifs. CBS forms filamentous assemblies that are allosterically tunable by SAM. Alternative reactions can generate H2S through condensation of cysteine with homocysteine. CBS deficiency causes classical homocystinuria, characterized by hyperhomocysteinemia with multi-system manifestations including vascular, ocular, skeletal, and neurological complications.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004122 cystathionine beta-synthase activity | IBA GO_REF:0000033 | ACCEPT | Summary: CBS activity is the defining function of this enzyme. The IBA annotation is phylogenetically well-supported across multiple organisms including yeast, mouse, and human. Reason: Cystathionine beta-synthase activity (EC 4.2.1.22) is the core enzymatic function of CBS. The enzyme catalyzes the PLP-dependent condensation of L-serine and L-homocysteine to form cystathionine. This is the canonical, rate-limiting step of the transsulfuration pathway. IBA annotation is well-supported by phylogenetic inference across multiple organisms. Supporting Evidence: PMID:7929220 The first committed step of transsulfuration is catalyzed by cystathionine beta-synthase (CBS), a known pyridoxal 5'-phosphate (PLP) enzyme PMID:11483494 Cystathionine beta-synthase (CBS) is a unique heme- containing enzyme that catalyzes a pyridoxal 5'-phosphate (PLP)-dependent condensation of serine and homocysteine to give cystathionine file:human/CBS/CBS-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0004122 cystathionine beta-synthase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation consistent with the experimentally validated core function. Reason: This IEA annotation is consistent with the experimentally-validated primary enzymatic activity. Multiple IDA annotations exist supporting this term. Supporting Evidence: PMID:7929220 The first committed step of transsulfuration is catalyzed by cystathionine beta-synthase (CBS), a known pyridoxal 5'-phosphate (PLP) enzyme |
| GO:0004122 cystathionine beta-synthase activity | IDA PMID:23981774 Characterization of two pathogenic mutations in cystathionin... | ACCEPT | Summary: Direct experimental demonstration of CBS activity in the context of characterizing pathogenic mutations. Reason: The study directly measured CBS catalytic activity when characterizing wild-type and mutant proteins expressed in prokaryotic and eukaryotic cells. Supporting Evidence: PMID:23981774 Cystathionine beta-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine |
| GO:0004122 cystathionine beta-synthase activity | IDA PMID:22985361 Human cystathionine Ξ²-synthase (CBS) contains two classes of... | ACCEPT | Summary: Direct enzyme activity assays in the context of SAM regulation studies. Reason: The study measured CBS enzyme activity to characterize SAM-mediated allosteric activation. Supporting Evidence: PMID:22985361 CBS (cystathionine beta-synthase) is a multidomain tetrameric enzyme essential in the regulation of homocysteine metabolism, whose activity is enhanced by the allosteric regulator SAM (S-adenosylmethionine) |
| GO:0004122 cystathionine beta-synthase activity | IDA PMID:24416422 Nitrite reductase activity and inhibition of HβS biogenesis ... | ACCEPT | Summary: CBS activity measured in context of nitrite reductase activity studies. Reason: The study measured canonical CBS activity (serine+homocysteine reaction) and showed inhibition by NO binding to heme. Supporting Evidence: PMID:24416422 CBS uses its PLP cofactor to catalyze Γβreplacement reactions that contribute to homocysteine clearance in the presence of either serine or cysteine as a co-substrate |
| GO:0004122 cystathionine beta-synthase activity | IDA PMID:7929220 Transsulfuration depends on heme in addition to pyridoxal 5'... | ACCEPT | Summary: Foundational study demonstrating CBS is both a PLP and heme-containing enzyme with cystathionine beta-synthase activity. Reason: This seminal paper demonstrated that human CBS expressed in E. coli has cystathionine beta-synthase activity and requires both heme and PLP cofactors. Supporting Evidence: PMID:7929220 delta-Aminolevulinate supplementation during bacterial growth increases both the heme saturation and the specific activity of the homogeneous enzyme more than 3-fold |
| GO:0004122 cystathionine beta-synthase activity | IDA PMID:18776696 Modulation of cystathionine beta-synthase activity by the Ar... | ACCEPT | Summary: CBS activity measured when studying effects of heme-site mutations. Reason: The study directly measured CBS enzymatic activity to characterize the effect of Arg-51 and Arg-224 mutations on enzyme function. Supporting Evidence: PMID:18776696 Human cystathionine beta-synthase (CBS) catalyzes a pyridoxal 5'-phosphate (PLP) dependent beta-replacement reaction to synthesize cystathionine from serine and homocysteine |
| GO:0004122 cystathionine beta-synthase activity | IDA PMID:19010420 Kinetic characterization of recombinant human cystathionine ... | ACCEPT | Summary: Detailed kinetic characterization of recombinant human CBS activity. Reason: This study provided detailed kinetic parameters for CBS-catalyzed cystathionine formation using a continuous assay. Supporting Evidence: PMID:19010420 Cystathionine beta-synthase (CBS) catalyzes the pyridoxal-50-phosphate-dependent condensation of L-serine and L-homocysteine to form L-cystathionine in the first step of the transsulfuration pathway |
| GO:0020037 heme binding | EXP PMID:29410458 Heme interaction of the intrinsically disordered N-terminal ... | ACCEPT | Summary: NMR and UV/Vis studies demonstrating heme binding to the intrinsically disordered N-terminal region of CBS via a CP-motif. Reason: CBS is a unique heme-binding PLP enzyme. This study demonstrated a second heme-binding site in the N-terminal intrinsically disordered region involving Cys15 and His22, in addition to the canonical Cys52/His65 site. Supporting Evidence: PMID:29410458 The heme-dependent protein CBS is part of regulatory pathways also involving the gasotransmitter hydrogen sulfide |
| GO:0020037 heme binding | IDA PMID:24515102 NO* binds human cystathionine Ξ²-synthase quickly and tightly... | ACCEPT | Summary: Spectroscopic characterization of heme binding and gas molecule interactions at the CBS heme site. Reason: The study characterized heme binding kinetics and showed that NO binds tightly to the ferrous CBS heme. Supporting Evidence: PMID:24515102 The hexa-coordinate heme in the H2S-generating human enzyme cystathionine Ξ²-synthase (CBS) acts as a redox-sensitive regulator that impairs CBS activity upon binding of NO(β’) or CO at the reduced iron |
| GO:0020037 heme binding | IDA PMID:7929220 Transsulfuration depends on heme in addition to pyridoxal 5'... | ACCEPT | Summary: Foundational demonstration that CBS is a heme protein with 1:1 stoichiometry. Reason: This seminal paper demonstrated that CBS binds heme b, with 1 mol of heme per 63-kDa subunit, and that heme is required for PLP binding. Supporting Evidence: PMID:7929220 We now confirm the presence of heme b in rat and human liver CBS PMID:7929220 1 mol of the 63-kDa CBS subunit binds 1 mol of each (heme and PLP) |
| GO:0020037 heme binding | IMP PMID:18776696 Modulation of cystathionine beta-synthase activity by the Ar... | ACCEPT | Summary: Mutational analysis demonstrating functional importance of heme-protein interactions. Reason: The study showed that mutations affecting heme-propionate interactions (Arg-51, Arg-224) decrease CBS activity by approximately 50%, demonstrating functional heme binding. Supporting Evidence: PMID:18776696 The enzyme is unique in bearing not only a catalytically important PLP but also heme PMID:18776696 the arginine mutations decrease CBS activity by approximately 50% |
| GO:0030170 pyridoxal phosphate binding | IDA PMID:7929220 Transsulfuration depends on heme in addition to pyridoxal 5'... | ACCEPT | Summary: CBS binds PLP as essential catalytic cofactor; heme is required for PLP binding. Reason: CBS is a PLP-dependent enzyme and the study demonstrated stoichiometric PLP binding that is dependent on heme. Supporting Evidence: PMID:7929220 The first committed step of transsulfuration is catalyzed by cystathionine beta-synthase (CBS), a known pyridoxal 5'-phosphate (PLP) enzyme PMID:7929220 The presence of heme is required for PLP binding, and the amount of PLP bound is limited by the heme content |
| GO:0030170 pyridoxal phosphate binding | IDA PMID:18776696 Modulation of cystathionine beta-synthase activity by the Ar... | ACCEPT | Summary: PLP binding demonstrated in context of heme-site mutation studies. Reason: The study confirms PLP binding and shows structural changes in heme vicinity affect PLP-dependent activity at a distance of 20 Angstroms. Supporting Evidence: PMID:18776696 The results indicate that structural changes in the heme vicinity are transmitted to PLP existing 20 A away from heme |
| GO:1904047 S-adenosyl-L-methionine binding | IDA PMID:22985361 Human cystathionine Ξ²-synthase (CBS) contains two classes of... | ACCEPT | Summary: Detailed characterization of SAM binding sites in CBS regulatory domain using calorimetric methods. Reason: This study identified two classes of SAM-binding sites in the C-terminal regulatory domain: high-affinity sites involved in kinetic stabilization and low-affinity sites involved in enzyme activation. Supporting Evidence: PMID:22985361 We found two sets of SAM-binding sites in the C-terminal regulatory domain with different structural and energetic features: a high affinity set of two sites, probably involved in kinetic stabilization of the regulatory domain, and a low affinity set of four sites, which are involved in the enzyme activation |
| GO:0070026 nitric oxide binding | IDA PMID:24416422 Nitrite reductase activity and inhibition of HβS biogenesis ... | ACCEPT | Summary: CBS binds NO at its heme, forming FeII-NO complex that inhibits enzyme activity. Reason: The study demonstrated NO binding to ferrous CBS heme using spectroscopic methods, showing formation of five-coordinate FeII-NO CBS complex. Supporting Evidence: PMID:24416422 Reaction of 10 Β΅M FeII-CBS with 10 mM nitrite under anaerobic conditions, showed time- and nitrite concentration-dependent changes in the heme spectrum consistent with formation of FeII-NO CBS |
| GO:0070026 nitric oxide binding | IDA PMID:24515102 NO* binds human cystathionine Ξ²-synthase quickly and tightly... | ACCEPT | Summary: Detailed kinetic characterization of NO binding to CBS heme showing tight, quick binding. Reason: This study showed NO binds tightly (Kd less than 0.23 microM) and quickly (kon approx. 8x10^3 M-1 s-1) to ferrous CBS heme. Supporting Evidence: PMID:24515102 We found that NO(β’) binds tightly to the ferrous CBS heme, with an apparent Kd β€ 0.23 ΞΌm |
| GO:0070025 carbon monoxide binding | IDA PMID:24515102 NO* binds human cystathionine Ξ²-synthase quickly and tightly... | ACCEPT | Summary: CO binds to ferrous CBS heme and inhibits enzyme activity. Reason: The study demonstrated CO binding to CBS heme, showing that NO ligand can be displaced by CO, and referenced previous work on CO-mediated CBS inhibition. Supporting Evidence: PMID:24515102 The hexa-coordinate heme in the H2S-generating human enzyme cystathionine Ξ²-synthase (CBS) acts as a redox-sensitive regulator that impairs CBS activity upon binding of NO(β’) or CO at the reduced iron |
| GO:0019825 oxygen binding | IDA PMID:24515102 NO* binds human cystathionine Ξ²-synthase quickly and tightly... | ACCEPT | Summary: CBS heme can bind oxygen; study characterized gas molecule binding at CBS heme. Reason: The study characterized CBS heme reactivity with various ligands including oxygen; ferrous CBS is rapidly oxidized by oxygen. Supporting Evidence: PMID:24515102 The hexa-coordinate heme in the H2S-generating human enzyme cystathionine beta-synthase (CBS) acts as a redox-sensitive regulator |
| GO:0050421 nitrite reductase (NO-forming) activity | IDA PMID:24416422 Nitrite reductase activity and inhibition of HβS biogenesis ... | KEEP AS NON CORE | Summary: CBS demonstrated to have nitrite reductase activity, generating NO from nitrite via its heme cofactor. Reason: While experimentally validated, this is not the core enzymatic function of CBS. The nitrite reductase activity represents an alternative reaction catalyzed by the CBS heme that may have regulatory significance for H2S production and NO signaling. The physiological relevance requires high nitrite concentrations. Supporting Evidence: PMID:24416422 In this study, we have identified human cystathionine Γ-synthase (CBS) as a new player in nitrite reduction with implications for the nitrite-dependent control of HβS production PMID:24416422 This novel activity of CBS exploits the catalytic property of its unusual heme cofactor to reduce nitrite and generate NO |
| GO:0003824 catalytic activity | IEA GO_REF:0000043 | ACCEPT | Summary: Parent term inferred from UniProt keyword mapping. Reason: CBS is an enzyme; this general parent term is correct but less informative than the specific cystathionine beta-synthase activity term. Supporting Evidence: PMID:7929220 The first committed step of transsulfuration is catalyzed by cystathionine beta-synthase (CBS) |
| GO:0016829 lyase activity | IEA GO_REF:0000043 | ACCEPT | Summary: CBS belongs to lyase family (EC 4.2.1.22). Reason: CBS is classified as a lyase (EC 4.2.1.22) that catalyzes a beta-replacement reaction eliminating water. This is a correct parent term. Supporting Evidence: PMID:11483494 Cystathionine beta-synthase (CBS) is a unique heme- containing enzyme that catalyzes a pyridoxal 5'-phosphate (PLP)-dependent condensation of serine and homocysteine to give cystathionine |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: CBS binds heme iron; this parent term captures that property. Reason: CBS contains a heme b cofactor with iron. The more specific term 'heme binding' is also annotated, but this parent term is technically correct. Supporting Evidence: PMID:7929220 We now confirm the presence of heme b in rat and human liver CBS |
| GO:0072341 modified amino acid binding | IDA PMID:20031578 Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma... | UNDECIDED | Summary: GWAS study associating CBS variants with homocysteine levels; homocysteine is a modified amino acid substrate. Reason: This annotation appears to come from a genome-wide association study identifying CBS variants associated with plasma homocysteine levels. While CBS does bind homocysteine as a substrate, this IDA evidence from a GWAS is not the typical direct biochemical demonstration expected for a binding annotation. The evidence code may be misapplied. Supporting Evidence: PMID:20031578 CBS catalyses the first step in the transsulfuration pathway of homocysteine catabolism |
| GO:0042803 protein homodimerization activity | IDA PMID:11483494 Structure of human cystathionine beta-synthase: a unique pyr... | ACCEPT | Summary: Crystal structure demonstrated CBS forms homodimers; the regulatory domain mediates higher-order oligomerization. Reason: The crystal structure shows CBS forms dimers through extensive inter-subunit contacts. CBS actually forms functional homotetramers and higher-order filaments, but dimerization is a prerequisite. Supporting Evidence: PMID:11483494 Here we present the X-ray crystal structure of a truncated form of the enzyme |
| GO:0042802 identical protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | ACCEPT | Summary: High-throughput interactome study detecting CBS self-interaction. Reason: CBS forms homotetramers and filaments; self-association is well-documented. High-throughput data consistent with known oligomeric state. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network. |
| GO:0042802 identical protein binding | IPI PMID:19447967 Shifted Transversal Design smart-pooling for high coverage i... | ACCEPT | Summary: Smart-pooling interactome study detecting CBS self-interaction. Reason: CBS self-associates to form tetramers and filaments; consistent with known biology. Supporting Evidence: PMID:19447967 Shifted Transversal Design smart-pooling for high coverage interactome mapping. |
| GO:0042802 identical protein binding | IPI PMID:21900206 A directed protein interaction network for investigating int... | ACCEPT | Summary: Signal transduction interactome study detecting CBS self-interaction. Reason: CBS self-associates; consistent with structural data. Supporting Evidence: PMID:21900206 A directed protein interaction network for investigating intracellular signal transduction. |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | ACCEPT | Summary: Proteome-scale interactome study detecting CBS self-interaction. Reason: CBS forms oligomers; self-interaction is well-established. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0042802 identical protein binding | IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... | ACCEPT | Summary: Massively parallel cloning study detecting CBS self-interaction. Reason: CBS oligomerization is well-characterized structurally. Supporting Evidence: PMID:25502805 eCollection 2014 Dec. |
| GO:0042802 identical protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | ACCEPT | Summary: Study of protein interactions disrupted by genetic variants. Reason: CBS self-association is well-documented; disease mutations can affect oligomerization. Supporting Evidence: PMID:23981774 Gel exclusion chromatography demonstrated a tendency of the T87N mutant to aggregate while the distribution of the D234N mutant was similar to wild-type enzyme PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome study detecting CBS protein interactions. Reason: 'Protein binding' is too general and uninformative. More specific terms exist for CBS interactions (e.g., identical protein binding, enzyme binding, ubiquitin protein ligase binding). High-throughput data without specific interactor context does not justify this broad annotation. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network. |
| GO:0005515 protein binding | IPI PMID:21653829 Protein interactome reveals converging molecular pathways am... | MARK AS OVER ANNOTATED | Summary: Autism disorder interactome study. Reason: 'Protein binding' is uninformative. This high-throughput interactome data does not provide specific biological context for the interaction. Supporting Evidence: PMID:21653829 Protein interactome reveals converging molecular pathways among autism disorders. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Proteome-scale human interactome network study. Reason: 'Protein binding' is too general. More specific binding terms should be used when the nature of the interaction is known. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:27107014 An inter-species protein-protein interaction network across ... | MARK AS OVER ANNOTATED | Summary: Inter-species protein interaction network study. Reason: 'Protein binding' is uninformative without specific interaction context. Supporting Evidence: PMID:27107014 An inter-species protein-protein interaction network across vast evolutionary distance. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: Study of genetic variants disrupting protein interactions. Reason: 'Protein binding' is too general. The study of interaction disruption by variants is valuable but does not justify this broad annotation. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Reference map of human binary protein interactome. Reason: 'Protein binding' provides no specific information about CBS function. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Neurodegenerative disease interactome study. Reason: 'Protein binding' is uninformative. More specific terms should be used. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0005515 protein binding | IPI PMID:17087506 Human cystathionine beta-synthase is a target for sumoylatio... | MODIFY | Summary: Study demonstrating CBS is target for sumoylation and interacts with sumoylation pathway components. Reason: While this publication supports protein binding, more specific terms are warranted. The study identified interactions with Ubc9, PIAS1, PIAS3, Pc2, and RanBPM. The 'ubiquitin protein ligase binding' annotation is more informative. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:17087506 Human cystathionine beta-synthase is a target for sumoylation. |
| GO:0019899 enzyme binding | IPI PMID:17087506 Human cystathionine beta-synthase is a target for sumoylatio... | ACCEPT | Summary: CBS interacts with enzymes in the sumoylation pathway (Ubc9, PIAS proteins). Reason: CBS was shown to interact with Ubc9 (E2 conjugating enzyme) and PIAS proteins (E3 ligases) in the sumoylation pathway. Supporting Evidence: PMID:17087506 Human cystathionine beta-synthase is a target for sumoylation. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:17087506 Human cystathionine beta-synthase is a target for sumoylatio... | ACCEPT | Summary: CBS interacts with SUMO/ubiquitin E3 ligases PIAS1, PIAS3, Pc2. Reason: The study identified CBS interaction with PIAS1, PIAS3, and Pc2, which are E3 ligases in the sumoylation/ubiquitination pathway. CBS is sumoylated at Lys-211. Supporting Evidence: PMID:17087506 Human cystathionine beta-synthase is a target for sumoylation. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for cytoplasmic localization consistent with CBS function in transsulfuration pathway. Reason: CBS is primarily a cytoplasmic enzyme functioning in the transsulfuration pathway. IBA annotation is phylogenetically supported. Supporting Evidence: PMID:23981774 the wild-type protein was homogeneously distributed inside the cell |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation consistent with experimental evidence for cytoplasmic localization. Reason: Cytoplasmic localization is well-supported by IDA evidence. Supporting Evidence: PMID:23981774 the wild-type protein was homogeneously distributed inside the cell |
| GO:0005737 cytoplasm | IDA PMID:23981774 Characterization of two pathogenic mutations in cystathionin... | ACCEPT | Summary: Immunofluorescence microscopy showing wild-type CBS is homogeneously distributed in the cytoplasm. Reason: Direct visualization by immunofluorescence shows wild-type CBS has homogeneous cytoplasmic distribution in HEK-293 cells. Supporting Evidence: PMID:23981774 Using immunofluorescence microscopy, an unexpected difference in intracellular localization was observed between the wild-type and mutant proteins |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1614524 | ACCEPT | Summary: Reactome annotation for cytosolic CBS tetramers catalyzing cystathionine formation. Reason: CBS is a soluble enzyme functioning in the cytosol. Reactome pathway annotation is consistent with biochemical evidence. Supporting Evidence: PMID:23981774 the wild-type protein was homogeneously distributed inside the cell |
| GO:0005829 cytosol | HDA PMID:16780588 Cell array-based intracellular localization screening reveal... | ACCEPT | Summary: Cell array-based localization screening showing cytosolic CBS. Reason: High-throughput localization data showing cytosolic CBS is consistent with its known function as a soluble cytoplasmic enzyme. Supporting Evidence: PMID:23981774 the wild-type protein was homogeneously distributed inside the cell PMID:16780588 Cell array-based intracellular localization screening reveals novel functional features of human chromosome 21 proteins. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA annotation based on UniProt subcellular location vocabulary. Reason: Nuclear localization of CBS has been demonstrated experimentally (PMID:17087506), where sumoylated CBS was found in the nucleus associated with nuclear scaffold. This represents a non-core localization related to regulatory functions. |
| GO:0005634 nucleus | IDA PMID:17087506 Human cystathionine beta-synthase is a target for sumoylatio... | KEEP AS NON CORE | Summary: Direct evidence for nuclear CBS localization, particularly sumoylated form associated with nuclear scaffold. Reason: While CBS is primarily cytoplasmic, the sumoylated form localizes to the nucleus. This represents a non-core localization, likely related to regulatory functions distinct from the primary transsulfuration pathway. Supporting Evidence: PMID:17087506 Human cystathionine beta-synthase is a target for sumoylation. |
| GO:0006535 L-cysteine biosynthetic process from L-serine | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for involvement in cysteine biosynthesis from serine via the transsulfuration pathway. Reason: CBS catalyzes the first step of the reverse transsulfuration pathway, which ultimately leads to cysteine synthesis from serine (via cystathionine intermediate). This is a core function. Supporting Evidence: PMID:24416422 The Γ-replacement of serine with homocysteine represents the cannonical reaction in the transsulfuration pathway |
| GO:0006535 L-cysteine biosynthetic process from L-serine | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based annotation consistent with CBS function in transsulfuration. Reason: CBS function in the transsulfuration pathway leads to cysteine biosynthesis. Supporting Evidence: PMID:24416422 CBS uses its PLP cofactor to catalyze Γβreplacement reactions that contribute to homocysteine clearance in the presence of either serine or cysteine as a co-substrate |
| GO:0019343 L-cysteine biosynthetic process via L-cystathionine | IEA GO_REF:0000002 | ACCEPT | Summary: Correct annotation specifying the cystathionine intermediate in cysteine biosynthesis. Reason: This is more specific than GO:0006535 and correctly captures that cysteine is produced via the cystathionine intermediate generated by CBS. Supporting Evidence: PMID:11483494 Cystathionine beta-synthase (CBS) is a unique heme- containing enzyme that catalyzes a pyridoxal 5'-phosphate (PLP)-dependent condensation of serine and homocysteine to give cystathionine |
| GO:0019344 L-cysteine biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: General cysteine biosynthesis term applicable to CBS function. Reason: CBS participates in cysteine biosynthesis through the transsulfuration pathway. This is a correct but less specific parent term. Supporting Evidence: PMID:24416422 CBS uses its PLP cofactor to catalyze Γβreplacement reactions that contribute to homocysteine clearance |
| GO:0019344 L-cysteine biosynthetic process | IDA PMID:24416422 Nitrite reductase activity and inhibition of HβS biogenesis ... | ACCEPT | Summary: Direct evidence for CBS role in cysteine biosynthesis through transsulfuration. Reason: The study demonstrates CBS produces cystathionine from serine and homocysteine, which is subsequently converted to cysteine by cystathionase. Supporting Evidence: PMID:24416422 Cystathionine, a product of the canonical serine+homocysteine or the noncanonical cysteine+homocysteine reactions, is cleaved by cystathionase to cysteine |
| GO:0019346 transsulfuration | IEA GO_REF:0000107 | ACCEPT | Summary: CBS catalyzes the first step of transsulfuration; this is its core pathway context. Reason: Transsulfuration is the core metabolic pathway in which CBS functions. CBS catalyzes the first and rate-limiting step. Supporting Evidence: PMID:7929220 The first committed step of transsulfuration is catalyzed by cystathionine beta-synthase (CBS) |
| GO:0050667 homocysteine metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: CBS uses homocysteine as substrate; central to homocysteine clearance. Reason: CBS is the primary enzyme for homocysteine clearance through the transsulfuration pathway. Homocysteine is a direct substrate. Supporting Evidence: PMID:22985361 CBS (cystathionine beta-synthase) is a multidomain tetrameric enzyme essential in the regulation of homocysteine metabolism |
| GO:0050667 homocysteine metabolic process | IDA PMID:23981774 Characterization of two pathogenic mutations in cystathionin... | ACCEPT | Summary: Direct demonstration of CBS role in homocysteine metabolism. Reason: The study characterizes CBS mutants in context of homocystinuria, a disease of homocysteine metabolism caused by CBS deficiency. Supporting Evidence: PMID:23981774 Homocystinuria is an autosomal recessive disorder commonly caused by a deficiency of CBS activity |
| GO:0050667 homocysteine metabolic process | IDA PMID:20031578 Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma... | ACCEPT | Summary: GWAS identifying CBS as genetic determinant of plasma homocysteine levels. Reason: GWAS data supports CBS role in homocysteine metabolism; variants at CBS locus significantly associate with plasma homocysteine. Supporting Evidence: PMID:20031578 CBS catalyses the first step in the transsulfuration pathway of homocysteine catabolism |
| GO:0050667 homocysteine metabolic process | IDA PMID:19010420 Kinetic characterization of recombinant human cystathionine ... | ACCEPT | Summary: Kinetic characterization of CBS with homocysteine as substrate. Reason: The study provides detailed kinetic parameters for CBS-catalyzed reactions using L-homocysteine as substrate. Supporting Evidence: PMID:19010420 Cystathionine beta-synthase (CBS) catalyzes the pyridoxal-50-phosphate-dependent condensation of L-serine and L-homocysteine to form L-cystathionine |
| GO:0043418 L-homocysteine catabolic process | IDA PMID:24416422 Nitrite reductase activity and inhibition of HβS biogenesis ... | ACCEPT | Summary: CBS consumes/catabolizes homocysteine in the transsulfuration pathway. Reason: CBS converts homocysteine to cystathionine, effectively catabolizing this potentially toxic metabolite. Supporting Evidence: PMID:24416422 CBS uses its PLP cofactor to catalyze Γβreplacement reactions that contribute to homocysteine clearance |
| GO:0043418 L-homocysteine catabolic process | IDA PMID:18776696 Modulation of cystathionine beta-synthase activity by the Ar... | ACCEPT | Summary: CBS activity measured using homocysteine catabolism. Reason: The study measured CBS activity in the reaction consuming homocysteine to form cystathionine. Supporting Evidence: PMID:18776696 Human cystathionine beta-synthase (CBS) catalyzes a pyridoxal 5'-phosphate (PLP) dependent beta-replacement reaction to synthesize cystathionine from serine and homocysteine |
| GO:0006563 L-serine metabolic process | IDA PMID:19010420 Kinetic characterization of recombinant human cystathionine ... | ACCEPT | Summary: CBS uses L-serine as co-substrate in cystathionine synthesis. Reason: L-serine is the primary co-substrate with homocysteine in the CBS-catalyzed canonical reaction. Supporting Evidence: PMID:19010420 Cystathionine beta-synthase (CBS) catalyzes the pyridoxal-50-phosphate-dependent condensation of L-serine and L-homocysteine to form L-cystathionine |
| GO:0006565 L-serine catabolic process | IDA PMID:18776696 Modulation of cystathionine beta-synthase activity by the Ar... | ACCEPT | Summary: CBS consumes L-serine in cystathionine synthesis reaction. Reason: The canonical CBS reaction consumes L-serine, condensing it with homocysteine. Supporting Evidence: PMID:18776696 Human cystathionine beta-synthase (CBS) catalyzes a pyridoxal 5'-phosphate (PLP) dependent beta-replacement reaction to synthesize cystathionine from serine and homocysteine |
| GO:0006534 cysteine metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: CBS contributes to cysteine metabolism through transsulfuration pathway. Reason: CBS is in the pathway leading to cysteine synthesis; also can use cysteine as alternative substrate for H2S production. Supporting Evidence: PMID:15520012 the CBS enzyme can efficiently produce H2S via a beta-replacement reaction in which cysteine is condensed with homocysteine to form cystathionine and H2S |
| GO:0019448 L-cysteine catabolic process | IDA PMID:15520012 Production of the neuromodulator H2S by cystathionine beta-s... | ACCEPT | Summary: CBS can use cysteine as alternative substrate, condensing it with homocysteine to produce H2S. Reason: CBS can catalyze a beta-replacement reaction using cysteine instead of serine, consuming cysteine to produce cystathionine and H2S. Supporting Evidence: PMID:15520012 the CBS enzyme can efficiently produce H2S via a beta-replacement reaction in which cysteine is condensed with homocysteine to form cystathionine and H2S |
| GO:0044272 sulfur compound biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: CBS functions in sulfur metabolism; produces cystathionine (sulfur-containing) and H2S. Reason: CBS is a key enzyme in sulfur amino acid metabolism, producing the sulfur-containing compound cystathionine and contributing to H2S biogenesis. Supporting Evidence: PMID:29410458 The lyase CBS acts in the transsulfuration pathway and has a central role in the mammalian sulfur metabolism |
| GO:0008652 amino acid biosynthetic process | IEA GO_REF:0000043 | ACCEPT | Summary: CBS contributes to cysteine (amino acid) biosynthesis. Reason: CBS functions in the pathway leading to cysteine biosynthesis; this is a correct but general parent term. Supporting Evidence: PMID:24416422 Cystathionine, a product of the canonical serine+homocysteine or the noncanonical cysteine+homocysteine reactions, is cleaved by cystathionase to cysteine |
| GO:0070814 hydrogen sulfide biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: CBS contributes to H2S biogenesis through alternative reactions. Reason: CBS can produce H2S through beta-replacement of cysteine with homocysteine. This is a validated alternative reaction. Supporting Evidence: PMID:15520012 the CBS enzyme can efficiently produce H2S via a beta-replacement reaction in which cysteine is condensed with homocysteine to form cystathionine and H2S |
| GO:0070814 hydrogen sulfide biosynthetic process | IDA PMID:24416422 Nitrite reductase activity and inhibition of HβS biogenesis ... | ACCEPT | Summary: Direct measurement of H2S production by CBS using cysteine+homocysteine substrates. Reason: The study directly measured CBS-dependent H2S production using lead acetate assay with cysteine and homocysteine as substrates. Supporting Evidence: PMID:24416422 In addition to the production of cystathionine in the canonical reaction, CBS generates H2S using alternative substrates such as cysteine or cysteine+homocysteine |
| GO:0070814 hydrogen sulfide biosynthetic process | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence similarity-based annotation consistent with validated CBS H2S production. Reason: ISS annotation is consistent with direct experimental evidence for CBS-mediated H2S production. Supporting Evidence: PMID:15520012 the CBS enzyme can efficiently produce H2S via a beta-replacement reaction |
| GO:0070814 hydrogen sulfide biosynthetic process | IDA PMID:15520012 Production of the neuromodulator H2S by cystathionine beta-s... | ACCEPT | Summary: Definitive demonstration of H2S production by CBS via cysteine+homocysteine condensation. Reason: This study established that CBS produces H2S primarily through beta-replacement of cysteine with homocysteine, not through cysteine hydrolysis. Supporting Evidence: PMID:15520012 Here we show that the CBS enzyme can efficiently produce H2S via a beta-replacement reaction in which cysteine is condensed with homocysteine to form cystathionine and H2S PMID:15520012 The production of H2S by this reaction is at least 50 times more efficient than that produced by hydrolysis of cysteine alone via beta-elimination |
| GO:0031667 response to nutrient levels | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CBS is regulated by nutrient levels (SAM, B vitamins); filamentation is nutrient-responsive. Reason: CBS activity and oligomeric state respond to nutrient availability through SAM-mediated allosteric activation. This represents regulatory biology rather than core enzymatic function. Supporting Evidence: PMID:22985361 CBS (cystathionine beta-synthase) is a multidomain tetrameric enzyme essential in the regulation of homocysteine metabolism, whose activity is enhanced by the allosteric regulator SAM (S-adenosylmethionine) |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation suggesting CBS negatively regulates apoptosis, possibly via H2S signaling or antioxidant (glutathione) production. Reason: This represents a downstream/pleiotropic effect of CBS function rather than direct enzymatic activity. CBS deficiency leads to oxidative stress due to reduced glutathione; H2S has cytoprotective effects. This is a secondary consequence of the core metabolic function. Supporting Evidence: PMID:24416422 Cysteine in turn, is a substrate for H2S-generation by cystathionase, a major H2S producer, and a limiting substrate for glutathione synthesis |
| GO:0071456 cellular response to hypoxia | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CBS activity is regulated under hypoxic conditions via heme-mediated gas sensing. Reason: CBS heme can bind gaseous ligands (NO, CO, O2) and the nitrite reductase activity may be relevant under hypoxic conditions. This represents regulatory biology and non-core function. Supporting Evidence: PMID:24416422 The in vitro nitrite reductase activity of CBS raises the possibility that it might contribute to NO biogenesis from the nitrite pool particularly under hypoxic conditions |
| GO:0042262 DNA protection | IMP PMID:24534463 Homocysteine contribution to DNA damage in cystathionine Ξ²-s... | KEEP AS NON CORE | Summary: Study showing CBS deficiency leads to increased DNA damage due to elevated homocysteine. Reason: This annotation reflects that CBS deficiency causes DNA damage, likely due to homocysteine accumulation and oxidative stress. The 'DNA protection' annotation captures the consequence that functional CBS protects DNA indirectly by maintaining low homocysteine levels. This is a downstream pleiotropic effect. Supporting Evidence: PMID:24534463 We verified that DNA damage was significantly higher in the CBS-deficient patients under treatment PMID:24534463 the present data indicate that DNA damage occurs in treated CBS-deficient patients, possibly due to high Hcy levels |
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Download this section (compressed HTML)Q: What is the relative contribution of CBS vs CSE vs 3-MST to tissue-specific H2S production in humans?
Q: What is the physiological relevance of CBS filament formation and does it occur in vivo in human tissues?
Q: How does the interplay between NO/CO/H2S signaling affect CBS activity in different cellular contexts?
Experiment: Live-cell imaging of CBS oligomeric states using fluorescent protein fusions to determine if filamentation occurs physiologically
Experiment: Quantitative proteomics to identify CBS protein interaction partners with specific biological functions
Experiment: Tissue-specific metabolomics in CBS heterozygous carriers to understand genotype-phenotype relationships
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