id: P35520
gene_symbol: CBS
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
existing_annotations:
# ============================================================================
# MOLECULAR FUNCTION - Core Enzymatic Activity
# ============================================================================
- term:
    id: GO:0004122
    label: cystathionine beta-synthase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:7929220
      supporting_text: "The first committed step of transsulfuration is catalyzed by cystathionine beta-synthase (CBS), a known pyridoxal 5'-phosphate (PLP) enzyme"
    - reference_id: PMID:11483494
      supporting_text: "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"

    - reference_id: file:human/CBS/CBS-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0004122
    label: cystathionine beta-synthase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation consistent with the experimentally validated core function.
    action: ACCEPT
    reason: >-
      This IEA annotation is consistent with the experimentally-validated primary
      enzymatic
      activity. Multiple IDA annotations exist supporting this term.
    supported_by:
    - reference_id: PMID:7929220
      supporting_text: "The first committed step of transsulfuration is catalyzed by cystathionine beta-synthase (CBS), a known pyridoxal 5'-phosphate (PLP) enzyme"

- term:
    id: GO:0004122
    label: cystathionine beta-synthase activity
  evidence_type: IDA
  original_reference_id: PMID:23981774
  review:
    summary: >-
      Direct experimental demonstration of CBS activity in the context of characterizing
      pathogenic mutations.
    action: ACCEPT
    reason: >-
      The study directly measured CBS catalytic activity when characterizing wild-type
      and
      mutant proteins expressed in prokaryotic and eukaryotic cells.
    supported_by:
    - reference_id: PMID:23981774
      supporting_text: "Cystathionine beta-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine"

- term:
    id: GO:0004122
    label: cystathionine beta-synthase activity
  evidence_type: IDA
  original_reference_id: PMID:22985361
  review:
    summary: Direct enzyme activity assays in the context of SAM regulation studies.
    action: ACCEPT
    reason: >-
      The study measured CBS enzyme activity to characterize SAM-mediated allosteric
      activation.
    supported_by:
    - reference_id: PMID:22985361
      supporting_text: "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)"

- term:
    id: GO:0004122
    label: cystathionine beta-synthase activity
  evidence_type: IDA
  original_reference_id: PMID:24416422
  review:
    summary: CBS activity measured in context of nitrite reductase activity studies.
    action: ACCEPT
    reason: >-
      The study measured canonical CBS activity (serine+homocysteine reaction) and
      showed
      inhibition by NO binding to heme.
    supported_by:
    - reference_id: PMID:24416422
      supporting_text: "CBS uses its PLP cofactor to catalyze ß–replacement reactions that contribute to homocysteine clearance in the presence of either serine or cysteine as a co-substrate"

- term:
    id: GO:0004122
    label: cystathionine beta-synthase activity
  evidence_type: IDA
  original_reference_id: PMID:7929220
  review:
    summary: >-
      Foundational study demonstrating CBS is both a PLP and heme-containing enzyme
      with
      cystathionine beta-synthase activity.
    action: ACCEPT
    reason: >-
      This seminal paper demonstrated that human CBS expressed in E. coli has cystathionine
      beta-synthase activity and requires both heme and PLP cofactors.
    supported_by:
    - reference_id: PMID:7929220
      supporting_text: "delta-Aminolevulinate supplementation during bacterial growth increases both the heme saturation and the specific activity of the homogeneous enzyme more than 3-fold"

- term:
    id: GO:0004122
    label: cystathionine beta-synthase activity
  evidence_type: IDA
  original_reference_id: PMID:18776696
  review:
    summary: CBS activity measured when studying effects of heme-site mutations.
    action: ACCEPT
    reason: >-
      The study directly measured CBS enzymatic activity to characterize the effect
      of
      Arg-51 and Arg-224 mutations on enzyme function.
    supported_by:
    - reference_id: PMID:18776696
      supporting_text: "Human cystathionine beta-synthase (CBS) catalyzes a pyridoxal 5'-phosphate (PLP) dependent beta-replacement reaction to synthesize cystathionine from serine and homocysteine"

- term:
    id: GO:0004122
    label: cystathionine beta-synthase activity
  evidence_type: IDA
  original_reference_id: PMID:19010420
  review:
    summary: Detailed kinetic characterization of recombinant human CBS activity.
    action: ACCEPT
    reason: >-
      This study provided detailed kinetic parameters for CBS-catalyzed cystathionine
      formation using a continuous assay.
    supported_by:
    - reference_id: PMID:19010420
      supporting_text: "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"

# ============================================================================
# MOLECULAR FUNCTION - Cofactor Binding
# ============================================================================
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: EXP
  original_reference_id: PMID:29410458
  review:
    summary: >-
      NMR and UV/Vis studies demonstrating heme binding to the intrinsically disordered
      N-terminal region of CBS via a CP-motif.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:29410458
      supporting_text: "The heme-dependent protein CBS is part of regulatory pathways also involving the gasotransmitter hydrogen sulfide"

- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IDA
  original_reference_id: PMID:24515102
  review:
    summary: >-
      Spectroscopic characterization of heme binding and gas molecule interactions
      at the
      CBS heme site.
    action: ACCEPT
    reason: >-
      The study characterized heme binding kinetics and showed that NO binds tightly
      to
      the ferrous CBS heme.
    supported_by:
    - reference_id: PMID:24515102
      supporting_text: "The hexa-coordinate heme in the H2S-generating human enzyme cystathionine β-synthase (CBS) acts as a redox-sensitive regulator that impairs CBS activity upon binding of NO(•) or CO at the reduced iron"

- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IDA
  original_reference_id: PMID:7929220
  review:
    summary: Foundational demonstration that CBS is a heme protein with 1:1 stoichiometry.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:7929220
      supporting_text: "We now confirm the presence of heme b in rat and human liver CBS"
    - reference_id: PMID:7929220
      supporting_text: "1 mol of the 63-kDa CBS subunit binds 1 mol of each (heme and PLP)"

- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IMP
  original_reference_id: PMID:18776696
  review:
    summary: >-
      Mutational analysis demonstrating functional importance of heme-protein interactions.
    action: ACCEPT
    reason: >-
      The study showed that mutations affecting heme-propionate interactions (Arg-51,
      Arg-224)
      decrease CBS activity by approximately 50%, demonstrating functional heme
      binding.
    supported_by:
    - reference_id: PMID:18776696
      supporting_text: "The enzyme is unique in bearing not only a catalytically important PLP but also heme"
    - reference_id: PMID:18776696
      supporting_text: "the arginine mutations decrease CBS activity by approximately 50%"

- term:
    id: GO:0030170
    label: pyridoxal phosphate binding
  evidence_type: IDA
  original_reference_id: PMID:7929220
  review:
    summary: CBS binds PLP as essential catalytic cofactor; heme is required for PLP binding.
    action: ACCEPT
    reason: >-
      CBS is a PLP-dependent enzyme and the study demonstrated stoichiometric PLP
      binding
      that is dependent on heme.
    supported_by:
    - reference_id: PMID:7929220
      supporting_text: "The first committed step of transsulfuration is catalyzed by cystathionine beta-synthase (CBS), a known pyridoxal 5'-phosphate (PLP) enzyme"
    - reference_id: PMID:7929220
      supporting_text: "The presence of heme is required for PLP binding, and the amount of PLP bound is limited by the heme content"

- term:
    id: GO:0030170
    label: pyridoxal phosphate binding
  evidence_type: IDA
  original_reference_id: PMID:18776696
  review:
    summary: PLP binding demonstrated in context of heme-site mutation studies.
    action: ACCEPT
    reason: >-
      The study confirms PLP binding and shows structural changes in heme vicinity
      affect
      PLP-dependent activity at a distance of 20 Angstroms.
    supported_by:
    - reference_id: PMID:18776696
      supporting_text: "The results indicate that structural changes in the heme vicinity are transmitted to PLP existing 20 A away from heme"

- term:
    id: GO:1904047
    label: S-adenosyl-L-methionine binding
  evidence_type: IDA
  original_reference_id: PMID:22985361
  review:
    summary: >-
      Detailed characterization of SAM binding sites in CBS regulatory domain using
      calorimetric methods.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:22985361
      supporting_text: "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"

# ============================================================================
# MOLECULAR FUNCTION - Gas Molecule Binding
# ============================================================================
- term:
    id: GO:0070026
    label: nitric oxide binding
  evidence_type: IDA
  original_reference_id: PMID:24416422
  review:
    summary: CBS binds NO at its heme, forming FeII-NO complex that inhibits enzyme activity.
    action: ACCEPT
    reason: >-
      The study demonstrated NO binding to ferrous CBS heme using spectroscopic
      methods,
      showing formation of five-coordinate FeII-NO CBS complex.
    supported_by:
    - reference_id: PMID:24416422
      supporting_text: "Reaction of 10 µM 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"

- term:
    id: GO:0070026
    label: nitric oxide binding
  evidence_type: IDA
  original_reference_id: PMID:24515102
  review:
    summary: >-
      Detailed kinetic characterization of NO binding to CBS heme showing tight,
      quick binding.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24515102
      supporting_text: "We found that NO(•) binds tightly to the ferrous CBS heme, with an apparent Kd ≤ 0.23 μm"

- term:
    id: GO:0070025
    label: carbon monoxide binding
  evidence_type: IDA
  original_reference_id: PMID:24515102
  review:
    summary: CO binds to ferrous CBS heme and inhibits enzyme activity.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24515102
      supporting_text: "The hexa-coordinate heme in the H2S-generating human enzyme cystathionine β-synthase (CBS) acts as a redox-sensitive regulator that impairs CBS activity upon binding of NO(•) or CO at the reduced iron"

- term:
    id: GO:0019825
    label: oxygen binding
  evidence_type: IDA
  original_reference_id: PMID:24515102
  review:
    summary: >-
      CBS heme can bind oxygen; study characterized gas molecule binding at CBS
      heme.
    action: ACCEPT
    reason: >-
      The study characterized CBS heme reactivity with various ligands including
      oxygen;
      ferrous CBS is rapidly oxidized by oxygen.
    supported_by:
    - reference_id: PMID:24515102
      supporting_text: "The hexa-coordinate heme in the H2S-generating human enzyme cystathionine beta-synthase (CBS) acts as a redox-sensitive regulator"

# ============================================================================
# MOLECULAR FUNCTION - Nitrite Reductase Activity
# ============================================================================
- term:
    id: GO:0050421
    label: nitrite reductase (NO-forming) activity
  evidence_type: IDA
  original_reference_id: PMID:24416422
  review:
    summary: >-
      CBS demonstrated to have nitrite reductase activity, generating NO from nitrite
      via its heme cofactor.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:24416422
      supporting_text: "In this study, we have identified human cystathionine ß-synthase (CBS) as a new player in nitrite reduction with implications for the nitrite-dependent control of H₂S production"
    - reference_id: PMID:24416422
      supporting_text: "This novel activity of CBS exploits the catalytic property of its unusual heme cofactor to reduce nitrite and generate NO"

# ============================================================================
# MOLECULAR FUNCTION - General/Parent Terms
# ============================================================================
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Parent term inferred from UniProt keyword mapping.
    action: ACCEPT
    reason: >-
      CBS is an enzyme; this general parent term is correct but less informative
      than
      the specific cystathionine beta-synthase activity term.
    supported_by:
    - reference_id: PMID:7929220
      supporting_text: "The first committed step of transsulfuration is catalyzed by cystathionine beta-synthase (CBS)"

- term:
    id: GO:0016829
    label: lyase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: CBS belongs to lyase family (EC 4.2.1.22).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:11483494
      supporting_text: "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"

- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: CBS binds heme iron; this parent term captures that property.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:7929220
      supporting_text: "We now confirm the presence of heme b in rat and human liver CBS"

- term:
    id: GO:0072341
    label: modified amino acid binding
  evidence_type: IDA
  original_reference_id: PMID:20031578
  review:
    summary: >-
      GWAS study associating CBS variants with homocysteine levels; homocysteine
      is a
      modified amino acid substrate.
    action: UNDECIDED
    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.
    supported_by:
    - reference_id: PMID:20031578
      supporting_text: "CBS catalyses the first step in the transsulfuration pathway of homocysteine catabolism"

# ============================================================================
# MOLECULAR FUNCTION - Protein Binding
# ============================================================================
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:11483494
  review:
    summary: >-
      Crystal structure demonstrated CBS forms homodimers; the regulatory domain
      mediates higher-order oligomerization.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:11483494
      supporting_text: "Here we present the X-ray crystal structure of a truncated form of the enzyme"

- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  review:
    summary: High-throughput interactome study detecting CBS self-interaction.
    action: ACCEPT
    reason: >-
      CBS forms homotetramers and filaments; self-association is well-documented.
      High-throughput data consistent with known oligomeric state.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: Towards a proteome-scale map of the human protein-protein interaction network.

- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19447967
  review:
    summary: Smart-pooling interactome study detecting CBS self-interaction.
    action: ACCEPT
    reason: CBS self-associates to form tetramers and filaments; consistent with known biology.
    supported_by:
    - reference_id: PMID:19447967
      supporting_text: Shifted Transversal Design smart-pooling for high coverage interactome mapping.

- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21900206
  review:
    summary: Signal transduction interactome study detecting CBS self-interaction.
    action: ACCEPT
    reason: CBS self-associates; consistent with structural data.
    supported_by:
    - reference_id: PMID:21900206
      supporting_text: A directed protein interaction network for investigating intracellular signal transduction.

- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: Proteome-scale interactome study detecting CBS self-interaction.
    action: ACCEPT
    reason: CBS forms oligomers; self-interaction is well-established.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network.

- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25502805
  review:
    summary: Massively parallel cloning study detecting CBS self-interaction.
    action: ACCEPT
    reason: CBS oligomerization is well-characterized structurally.
    supported_by:
    - reference_id: PMID:25502805
      supporting_text: eCollection 2014 Dec.

- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  review:
    summary: Study of protein interactions disrupted by genetic variants.
    action: ACCEPT
    reason: CBS self-association is well-documented; disease mutations can affect oligomerization.
    supported_by:
    - reference_id: PMID:23981774
      supporting_text: "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"

    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  review:
    summary: High-throughput interactome study detecting CBS protein interactions.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: Towards a proteome-scale map of the human protein-protein interaction network.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21653829
  review:
    summary: Autism disorder interactome study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'Protein binding' is uninformative. This high-throughput interactome data
      does
      not provide specific biological context for the interaction.
    supported_by:
    - reference_id: PMID:21653829
      supporting_text: Protein interactome reveals converging molecular pathways among autism disorders.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: Proteome-scale human interactome network study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'Protein binding' is too general. More specific binding terms should be used
      when the nature of the interaction is known.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27107014
  review:
    summary: Inter-species protein interaction network study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'Protein binding' is uninformative without specific interaction context.
    supported_by:
    - reference_id: PMID:27107014
      supporting_text: An inter-species protein-protein interaction network across vast evolutionary distance.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  review:
    summary: Study of genetic variants disrupting protein interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'Protein binding' is too general. The study of interaction disruption by variants
      is valuable but does not justify this broad annotation.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: Reference map of human binary protein interactome.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'Protein binding' provides no specific information about CBS function.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: Apr 8. A reference map of the human binary protein interactome.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: Neurodegenerative disease interactome study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'Protein binding' is uninformative. More specific terms should be used.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17087506
  review:
    summary: >-
      Study demonstrating CBS is target for sumoylation and interacts with sumoylation
      pathway components.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0031625
      label: ubiquitin protein ligase binding
    supported_by:
    - reference_id: PMID:17087506
      supporting_text: Human cystathionine beta-synthase is a target for sumoylation.

- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:17087506
  review:
    summary: CBS interacts with enzymes in the sumoylation pathway (Ubc9, PIAS proteins).
    action: ACCEPT
    reason: >-
      CBS was shown to interact with Ubc9 (E2 conjugating enzyme) and PIAS proteins
      (E3 ligases) in the sumoylation pathway.
    supported_by:
    - reference_id: PMID:17087506
      supporting_text: Human cystathionine beta-synthase is a target for sumoylation.

- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:17087506
  review:
    summary: CBS interacts with SUMO/ubiquitin E3 ligases PIAS1, PIAS3, Pc2.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:17087506
      supporting_text: Human cystathionine beta-synthase is a target for sumoylation.

# ============================================================================
# CELLULAR COMPONENT - Localization
# ============================================================================
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for cytoplasmic localization consistent with CBS function in
      transsulfuration pathway.
    action: ACCEPT
    reason: >-
      CBS is primarily a cytoplasmic enzyme functioning in the transsulfuration
      pathway.
      IBA annotation is phylogenetically supported.
    supported_by:
    - reference_id: PMID:23981774
      supporting_text: "the wild-type protein was homogeneously distributed inside the cell"

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation consistent with experimental evidence for cytoplasmic localization.
    action: ACCEPT
    reason: Cytoplasmic localization is well-supported by IDA evidence.
    supported_by:
    - reference_id: PMID:23981774
      supporting_text: "the wild-type protein was homogeneously distributed inside the cell"

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:23981774
  review:
    summary: >-
      Immunofluorescence microscopy showing wild-type CBS is homogeneously distributed
      in the cytoplasm.
    action: ACCEPT
    reason: >-
      Direct visualization by immunofluorescence shows wild-type CBS has homogeneous
      cytoplasmic distribution in HEK-293 cells.
    supported_by:
    - reference_id: PMID:23981774
      supporting_text: "Using immunofluorescence microscopy, an unexpected difference in intracellular localization was observed between the wild-type and mutant proteins"

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1614524
  review:
    summary: Reactome annotation for cytosolic CBS tetramers catalyzing cystathionine formation.
    action: ACCEPT
    reason: >-
      CBS is a soluble enzyme functioning in the cytosol. Reactome pathway annotation
      is consistent with biochemical evidence.
    supported_by:
    - reference_id: PMID:23981774
      supporting_text: "the wild-type protein was homogeneously distributed inside the cell"

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: HDA
  original_reference_id: PMID:16780588
  review:
    summary: Cell array-based localization screening showing cytosolic CBS.
    action: ACCEPT
    reason: >-
      High-throughput localization data showing cytosolic CBS is consistent with
      its known function as a soluble cytoplasmic enzyme.
    supported_by:
    - reference_id: PMID:23981774
      supporting_text: "the wild-type protein was homogeneously distributed inside the cell"

    - reference_id: PMID:16780588
      supporting_text: Cell array-based intracellular localization screening reveals novel functional features of human chromosome 21 proteins.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: IEA annotation based on UniProt subcellular location vocabulary.
    action: KEEP_AS_NON_CORE
    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.
    supported_by: []

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:17087506
  review:
    summary: >-
      Direct evidence for nuclear CBS localization, particularly sumoylated form
      associated with nuclear scaffold.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:17087506
      supporting_text: Human cystathionine beta-synthase is a target for sumoylation.

# ============================================================================
# BIOLOGICAL PROCESS - Core Pathway Functions
# ============================================================================
- term:
    id: GO:0006535
    label: L-cysteine biosynthetic process from L-serine
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for involvement in cysteine biosynthesis from serine via the
      transsulfuration pathway.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:24416422
      supporting_text: "The ß-replacement of serine with homocysteine represents the cannonical reaction in the transsulfuration pathway"

- term:
    id: GO:0006535
    label: L-cysteine biosynthetic process from L-serine
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: InterPro-based annotation consistent with CBS function in transsulfuration.
    action: ACCEPT
    reason: >-
      CBS function in the transsulfuration pathway leads to cysteine biosynthesis.
    supported_by:
    - reference_id: PMID:24416422
      supporting_text: "CBS uses its PLP cofactor to catalyze ß–replacement reactions that contribute to homocysteine clearance in the presence of either serine or cysteine as a co-substrate"

- term:
    id: GO:0019343
    label: L-cysteine biosynthetic process via L-cystathionine
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      Correct annotation specifying the cystathionine intermediate in cysteine biosynthesis.
    action: ACCEPT
    reason: >-
      This is more specific than GO:0006535 and correctly captures that cysteine
      is
      produced via the cystathionine intermediate generated by CBS.
    supported_by:
    - reference_id: PMID:11483494
      supporting_text: "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"

- term:
    id: GO:0019344
    label: L-cysteine biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: General cysteine biosynthesis term applicable to CBS function.
    action: ACCEPT
    reason: >-
      CBS participates in cysteine biosynthesis through the transsulfuration pathway.
      This is a correct but less specific parent term.
    supported_by:
    - reference_id: PMID:24416422
      supporting_text: "CBS uses its PLP cofactor to catalyze ß–replacement reactions that contribute to homocysteine clearance"

- term:
    id: GO:0019344
    label: L-cysteine biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:24416422
  review:
    summary: >-
      Direct evidence for CBS role in cysteine biosynthesis through transsulfuration.
    action: ACCEPT
    reason: >-
      The study demonstrates CBS produces cystathionine from serine and homocysteine,
      which is subsequently converted to cysteine by cystathionase.
    supported_by:
    - reference_id: PMID:24416422
      supporting_text: "Cystathionine, a product of the canonical serine+homocysteine or the noncanonical cysteine+homocysteine reactions, is cleaved by cystathionase to cysteine"

- term:
    id: GO:0019346
    label: transsulfuration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      CBS catalyzes the first step of transsulfuration; this is its core pathway
      context.
    action: ACCEPT
    reason: >-
      Transsulfuration is the core metabolic pathway in which CBS functions. CBS
      catalyzes
      the first and rate-limiting step.
    supported_by:
    - reference_id: PMID:7929220
      supporting_text: "The first committed step of transsulfuration is catalyzed by cystathionine beta-synthase (CBS)"

- term:
    id: GO:0050667
    label: homocysteine metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: CBS uses homocysteine as substrate; central to homocysteine clearance.
    action: ACCEPT
    reason: >-
      CBS is the primary enzyme for homocysteine clearance through the transsulfuration
      pathway. Homocysteine is a direct substrate.
    supported_by:
    - reference_id: PMID:22985361
      supporting_text: "CBS (cystathionine beta-synthase) is a multidomain tetrameric enzyme essential in the regulation of homocysteine metabolism"

- term:
    id: GO:0050667
    label: homocysteine metabolic process
  evidence_type: IDA
  original_reference_id: PMID:23981774
  review:
    summary: Direct demonstration of CBS role in homocysteine metabolism.
    action: ACCEPT
    reason: >-
      The study characterizes CBS mutants in context of homocystinuria, a disease
      of
      homocysteine metabolism caused by CBS deficiency.
    supported_by:
    - reference_id: PMID:23981774
      supporting_text: "Homocystinuria is an autosomal recessive disorder commonly caused by a deficiency of CBS activity"

- term:
    id: GO:0050667
    label: homocysteine metabolic process
  evidence_type: IDA
  original_reference_id: PMID:20031578
  review:
    summary: GWAS identifying CBS as genetic determinant of plasma homocysteine levels.
    action: ACCEPT
    reason: >-
      GWAS data supports CBS role in homocysteine metabolism; variants at CBS locus
      significantly associate with plasma homocysteine.
    supported_by:
    - reference_id: PMID:20031578
      supporting_text: "CBS catalyses the first step in the transsulfuration pathway of homocysteine catabolism"

- term:
    id: GO:0050667
    label: homocysteine metabolic process
  evidence_type: IDA
  original_reference_id: PMID:19010420
  review:
    summary: Kinetic characterization of CBS with homocysteine as substrate.
    action: ACCEPT
    reason: >-
      The study provides detailed kinetic parameters for CBS-catalyzed reactions
      using
      L-homocysteine as substrate.
    supported_by:
    - reference_id: PMID:19010420
      supporting_text: "Cystathionine beta-synthase (CBS) catalyzes the pyridoxal-50-phosphate-dependent condensation of L-serine and L-homocysteine to form L-cystathionine"

- term:
    id: GO:0043418
    label: L-homocysteine catabolic process
  evidence_type: IDA
  original_reference_id: PMID:24416422
  review:
    summary: CBS consumes/catabolizes homocysteine in the transsulfuration pathway.
    action: ACCEPT
    reason: >-
      CBS converts homocysteine to cystathionine, effectively catabolizing this
      potentially toxic metabolite.
    supported_by:
    - reference_id: PMID:24416422
      supporting_text: "CBS uses its PLP cofactor to catalyze ß–replacement reactions that contribute to homocysteine clearance"

- term:
    id: GO:0043418
    label: L-homocysteine catabolic process
  evidence_type: IDA
  original_reference_id: PMID:18776696
  review:
    summary: CBS activity measured using homocysteine catabolism.
    action: ACCEPT
    reason: >-
      The study measured CBS activity in the reaction consuming homocysteine to
      form
      cystathionine.
    supported_by:
    - reference_id: PMID:18776696
      supporting_text: "Human cystathionine beta-synthase (CBS) catalyzes a pyridoxal 5'-phosphate (PLP) dependent beta-replacement reaction to synthesize cystathionine from serine and homocysteine"

- term:
    id: GO:0006563
    label: L-serine metabolic process
  evidence_type: IDA
  original_reference_id: PMID:19010420
  review:
    summary: CBS uses L-serine as co-substrate in cystathionine synthesis.
    action: ACCEPT
    reason: >-
      L-serine is the primary co-substrate with homocysteine in the CBS-catalyzed
      canonical reaction.
    supported_by:
    - reference_id: PMID:19010420
      supporting_text: "Cystathionine beta-synthase (CBS) catalyzes the pyridoxal-50-phosphate-dependent condensation of L-serine and L-homocysteine to form L-cystathionine"

- term:
    id: GO:0006565
    label: L-serine catabolic process
  evidence_type: IDA
  original_reference_id: PMID:18776696
  review:
    summary: CBS consumes L-serine in cystathionine synthesis reaction.
    action: ACCEPT
    reason: >-
      The canonical CBS reaction consumes L-serine, condensing it with homocysteine.
    supported_by:
    - reference_id: PMID:18776696
      supporting_text: "Human cystathionine beta-synthase (CBS) catalyzes a pyridoxal 5'-phosphate (PLP) dependent beta-replacement reaction to synthesize cystathionine from serine and homocysteine"

- term:
    id: GO:0006534
    label: cysteine metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: CBS contributes to cysteine metabolism through transsulfuration pathway.
    action: ACCEPT
    reason: >-
      CBS is in the pathway leading to cysteine synthesis; also can use cysteine
      as
      alternative substrate for H2S production.
    supported_by:
    - reference_id: PMID:15520012
      supporting_text: "the CBS enzyme can efficiently produce H2S via a beta-replacement reaction in which cysteine is condensed with homocysteine to form cystathionine and H2S"

- term:
    id: GO:0019448
    label: L-cysteine catabolic process
  evidence_type: IDA
  original_reference_id: PMID:15520012
  review:
    summary: >-
      CBS can use cysteine as alternative substrate, condensing it with homocysteine
      to produce H2S.
    action: ACCEPT
    reason: >-
      CBS can catalyze a beta-replacement reaction using cysteine instead of serine,
      consuming cysteine to produce cystathionine and H2S.
    supported_by:
    - reference_id: PMID:15520012
      supporting_text: "the CBS enzyme can efficiently produce H2S via a beta-replacement reaction in which cysteine is condensed with homocysteine to form cystathionine and H2S"

- term:
    id: GO:0044272
    label: sulfur compound biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      CBS functions in sulfur metabolism; produces cystathionine (sulfur-containing)
      and H2S.
    action: ACCEPT
    reason: >-
      CBS is a key enzyme in sulfur amino acid metabolism, producing the sulfur-containing
      compound cystathionine and contributing to H2S biogenesis.
    supported_by:
    - reference_id: PMID:29410458
      supporting_text: "The lyase CBS acts in the transsulfuration pathway and has a central role in the mammalian sulfur metabolism"

- term:
    id: GO:0008652
    label: amino acid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: CBS contributes to cysteine (amino acid) biosynthesis.
    action: ACCEPT
    reason: >-
      CBS functions in the pathway leading to cysteine biosynthesis; this is a
      correct but general parent term.
    supported_by:
    - reference_id: PMID:24416422
      supporting_text: "Cystathionine, a product of the canonical serine+homocysteine or the noncanonical cysteine+homocysteine reactions, is cleaved by cystathionase to cysteine"

# ============================================================================
# BIOLOGICAL PROCESS - H2S Production
# ============================================================================
- term:
    id: GO:0070814
    label: hydrogen sulfide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: CBS contributes to H2S biogenesis through alternative reactions.
    action: ACCEPT
    reason: >-
      CBS can produce H2S through beta-replacement of cysteine with homocysteine.
      This is a validated alternative reaction.
    supported_by:
    - reference_id: PMID:15520012
      supporting_text: "the CBS enzyme can efficiently produce H2S via a beta-replacement reaction in which cysteine is condensed with homocysteine to form cystathionine and H2S"

- term:
    id: GO:0070814
    label: hydrogen sulfide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:24416422
  review:
    summary: Direct measurement of H2S production by CBS using cysteine+homocysteine substrates.
    action: ACCEPT
    reason: >-
      The study directly measured CBS-dependent H2S production using lead acetate
      assay
      with cysteine and homocysteine as substrates.
    supported_by:
    - reference_id: PMID:24416422
      supporting_text: "In addition to the production of cystathionine in the canonical reaction, CBS generates H2S using alternative substrates such as cysteine or cysteine+homocysteine"

- term:
    id: GO:0070814
    label: hydrogen sulfide biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Sequence similarity-based annotation consistent with validated CBS H2S production.
    action: ACCEPT
    reason: >-
      ISS annotation is consistent with direct experimental evidence for CBS-mediated
      H2S production.
    supported_by:
    - reference_id: PMID:15520012
      supporting_text: "the CBS enzyme can efficiently produce H2S via a beta-replacement reaction"

- term:
    id: GO:0070814
    label: hydrogen sulfide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:15520012
  review:
    summary: >-
      Definitive demonstration of H2S production by CBS via cysteine+homocysteine
      condensation.
    action: ACCEPT
    reason: >-
      This study established that CBS produces H2S primarily through beta-replacement
      of cysteine with homocysteine, not through cysteine hydrolysis.
    supported_by:
    - reference_id: PMID:15520012
      supporting_text: "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"
    - reference_id: PMID:15520012
      supporting_text: "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"

# ============================================================================
# BIOLOGICAL PROCESS - Regulatory/Pleiotropic Functions
# ============================================================================
- term:
    id: GO:0031667
    label: response to nutrient levels
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      CBS is regulated by nutrient levels (SAM, B vitamins); filamentation is
      nutrient-responsive.
    action: KEEP_AS_NON_CORE
    reason: >-
      CBS activity and oligomeric state respond to nutrient availability through
      SAM-mediated allosteric activation. This represents regulatory biology rather
      than core enzymatic function.
    supported_by:
    - reference_id: PMID:22985361
      supporting_text: "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)"

- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation suggesting CBS negatively regulates apoptosis, possibly via
      H2S signaling or antioxidant (glutathione) production.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:24416422
      supporting_text: "Cysteine in turn, is a substrate for H2S-generation by cystathionase, a major H2S producer, and a limiting substrate for glutathione synthesis"

- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      CBS activity is regulated under hypoxic conditions via heme-mediated gas sensing.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:24416422
      supporting_text: "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"

- term:
    id: GO:0042262
    label: DNA protection
  evidence_type: IMP
  original_reference_id: PMID:24534463
  review:
    summary: >-
      Study showing CBS deficiency leads to increased DNA damage due to elevated
      homocysteine.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:24534463
      supporting_text: "We verified that DNA damage was significantly higher in the CBS-deficient patients under treatment"
    - reference_id: PMID:24534463
      supporting_text: "the present data indicate that DNA damage occurs in treated CBS-deficient patients, possibly due to high Hcy levels"

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:7929220
  title: >-
    Transsulfuration depends on heme in addition to pyridoxal 5'-phosphate.
    Cystathionine beta-synthase is a heme protein.
  findings:
  - statement: CBS binds both heme b and PLP with 1:1 stoichiometry
    supporting_text: "1 mol of the 63-kDa CBS subunit binds 1 mol of each (heme and PLP)"
  - statement: Heme is required for PLP binding
    supporting_text: "The presence of heme is required for PLP binding, and the amount of PLP bound is limited by the heme content"
  - statement: Heme saturation correlates with specific activity
    supporting_text: "delta-Aminolevulinate supplementation during bacterial growth increases both the heme saturation and the specific activity of the homogeneous enzyme more than 3-fold"
- id: PMID:11483494
  title: >-
    Structure of human cystathionine beta-synthase: a unique pyridoxal
    5'-phosphate-dependent heme protein.
  findings:
  - statement: Crystal structure of truncated CBS determined
    supporting_text: "Here we present the X-ray crystal structure of a truncated form of the enzyme"
  - statement: CBS shares fold with O-acetylserine sulfhydrylase
    supporting_text: "CBS shares the same fold with O-acetylserine sulfhydrylase but it contains an additional N-terminal heme binding site"
  - statement: Contains N-terminal heme binding domain
    supporting_text: "CBS shares the same fold with O-acetylserine sulfhydrylase but it contains an additional N-terminal heme binding site"
- id: PMID:15520012
  title: >-
    Production of the neuromodulator H2S by cystathionine beta-synthase via
    the condensation of cysteine and homocysteine.
  findings:
  - statement: CBS produces H2S via cysteine+homocysteine beta-replacement
    supporting_text: "the CBS enzyme can efficiently produce H2S via a beta-replacement reaction in which cysteine is condensed with homocysteine to form cystathionine and H2S"
  - statement: H2S production 50x more efficient than cysteine hydrolysis
    supporting_text: "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"
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:16780588
  title: >-
    Cell array-based intracellular localization screening reveals novel
    functional features of human chromosome 21 proteins.
  findings: []
- id: PMID:17087506
  title: Human cystathionine beta-synthase is a target for sumoylation.
  findings:
  - statement: CBS interacts with Ubc9, PIAS1, PIAS3, Pc2, RanBPM
  - statement: CBS is sumoylated at Lys-211
  - statement: Sumoylated CBS localizes to nucleus
- id: PMID:18776696
  title: >-
    Modulation of cystathionine beta-synthase activity by the Arg-51 and
    Arg-224 mutations.
  findings:
  - statement: Arg-51 and Arg-224 interact with heme propionates
    supporting_text: "we performed mutagenesis of Arg-51 and Arg-224, which have hydrogen-bonding interactions with propionate side chains of the prosthetic group"
  - statement: Mutations decrease CBS activity by approximately 50%
    supporting_text: "the arginine mutations decrease CBS activity by approximately 50%"
  - statement: Structural changes at heme transmitted to PLP site
    supporting_text: "The results indicate that structural changes in the heme vicinity are transmitted to PLP existing 20 A away from heme"
- id: PMID:19010420
  title: Kinetic characterization of recombinant human cystathionine beta-synthase purified from E. coli.
  findings:
  - statement: Detailed kinetic parameters for CBS-catalyzed reactions
    supporting_text: "the steady-state kinetic parameters of hCBS, via global analysis, and revealed previously unreported substrate inhibition by L-Hcys"
  - statement: Substrate inhibition by L-homocysteine (Ki = 2.1 mM)
    supporting_text: "revealed previously unreported substrate inhibition by L-Hcys (K(i)(L-HCYS) = 2.1 +/- 0.2 mM)"
- id: PMID:19447967
  title: Shifted Transversal Design smart-pooling for high coverage interactome mapping.
  findings: []
- id: PMID:20031578
  title: >-
    Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma homocysteine
    in a healthy population: a genome-wide evaluation of 13 974 participants in
    the
    Women's Genome Health Study.
  findings:
  - statement: GWAS confirms CBS association with homocysteine levels
    supporting_text: "we confirm association with MTHFR (1p36.22; rs1801133; P=8.1 x 10(-35)) and CBS (21q22.3; rs6586282; P=3.2 x 10(-10))"
  - statement: CBS catalyzes first step of transsulfuration
    supporting_text: "CBS catalyses the first step in the transsulfuration pathway of homocysteine catabolism"
- id: PMID:21653829
  title: Protein interactome reveals converging molecular pathways among autism disorders.
  findings: []
- id: PMID:21900206
  title: A directed protein interaction network for investigating intracellular signal transduction.
  findings: []
- id: PMID:22985361
  title: >-
    Human cystathionine β-synthase (CBS) contains two classes of binding
    sites for S-adenosylmethionine (SAM): complex regulation of CBS activity and
    stability
    by SAM.
  findings:
  - statement: Two sets of SAM-binding sites identified
    supporting_text: "We found two sets of SAM-binding sites in the C-terminal regulatory domain with different structural and energetic features"
  - statement: High-affinity sites for kinetic stabilization
    supporting_text: "a high affinity set of two sites, probably involved in kinetic stabilization of the regulatory domain"
  - statement: Low-affinity sites for enzyme activation
    supporting_text: "a low affinity set of four sites, which are involved in the enzyme activation"
- id: PMID:23981774
  title: >-
    Characterization of two pathogenic mutations in cystathionine beta-synthase:
    different intracellular locations for wild-type and mutant proteins.
  findings:
  - statement: Wild-type CBS homogeneously distributed in cytoplasm
    supporting_text: "the wild-type protein was homogeneously distributed inside the cell"
  - statement: Mutants show altered localization (punctate)
    supporting_text: "While the T87N mutant exhibited a punctate appearance, the wild-type protein was homogeneously distributed inside the cell"
  - statement: Activity assays confirm CBS function
    supporting_text: "Residual activities obtained for the mutant proteins were 3.5% T87N and 43% D234N"
- id: PMID:24416422
  title: Nitrite reductase activity and inhibition of H₂S biogenesis by human cystathionine ß-synthase.
  findings:
  - statement: CBS has nitrite reductase activity via heme
    supporting_text: "In this study, we have identified human cystathionine ß-synthase (CBS) as a new player in nitrite reduction"
  - statement: NO binding to heme inhibits CBS activity
    supporting_text: "Binding of carbon monoxide (CO) or NO to the FeII-CBS heme inhibits enzyme activity"
  - statement: FeII-NO CBS inhibits H2S production by ~90%
    supporting_text: "Formation of FeII-NO CBS was correlated with ∼90% inhibition of H2S production in the presence of cysteine+homocysteine"
- id: PMID:24515102
  title: NO* binds human cystathionine β-synthase quickly and tightly.
  findings:
  - statement: NO binds tightly to ferrous CBS heme (Kd less than 0.23 microM)
    supporting_text: "We found that NO(•) binds tightly to the ferrous CBS heme, with an apparent Kd ≤ 0.23 μm"
  - statement: Quick binding (kon approx. 8x10^3 M-1 s-1)
    supporting_text: "at 25 °C, NO(•) binds quickly to CBS (k on ∼ 8 × 10(3) m(-1) s(-1))"
  - statement: Slow dissociation (koff approx. 0.003 s-1)
    supporting_text: "dissociates slowly from the enzyme (k off ∼ 0.003 s(-1))"
- id: PMID:24534463
  title: Homocysteine contribution to DNA damage in cystathionine β-synthase-deficient patients.
  findings:
  - statement: CBS-deficient patients have increased DNA damage
    supporting_text: "We verified that DNA damage was significantly higher in the CBS-deficient patients under treatment"
  - statement: Homocysteine induces DNA damage in concentration-dependent manner
    supporting_text: "the in vitro study showed a concentration-dependent effect of Hcy inducing DNA damage"
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:25502805
  title: >-
    A massively parallel pipeline to clone DNA variants and examine molecular
    phenotypes of human disease mutations.
  findings: []
- id: PMID:27107014
  title: An inter-species protein-protein interaction network across vast evolutionary distance.
  findings: []
- id: PMID:29410458
  title: Heme interaction of the intrinsically disordered N-terminal peptide segment of human cystathionine-β-synthase.
  findings:
  - statement: N-terminal 40 residues are intrinsically disordered
    supporting_text: "NMR spectroscopy revealed that the forty N-terminal residues constitute an intrinsically disordered region of the protein cystathionine-beta-synthase"
  - statement: Second heme-binding site via Cys15/His22 CP-motif
    supporting_text: "the disordered N-terminal region of CBS contributes heme-binding capacities via a second binding site, the CP-based motif at cysteine-15"
  - statement: Heme binding increases enzyme activity by approx. 30%
    supporting_text: "The functional assay reveals that this heme-binding site at cysteine-15 and histidine-22 as second axial heme ligand increases the efficacy of the enzyme by approx. 30%"
- id: PMID:31515488
  title: >-
    Extensive disruption of protein interactions by genetic variants across
    the allele frequency spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: >-
    Interactome Mapping Provides a Network of Neurodegenerative Disease
    Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: Reactome:R-HSA-1614524
  title: PXLP-CBS tetramers condenses HCYS and L-Ser to form L-Cystathionine
  findings: []
- id: file:human/CBS/CBS-deep-research-falcon.md
  title: Deep research report on CBS
  findings: []

core_functions:
- description: >-
    Primary enzymatic function catalyzing condensation of L-serine and L-homocysteine
    to form cystathionine, the first and rate-limiting step of transsulfuration.
  molecular_function:
    id: GO:0004122
    label: cystathionine beta-synthase activity
  directly_involved_in:
  - id: GO:0019346
    label: transsulfuration
  - id: GO:0043418
    label: L-homocysteine catabolic process
  locations:
  - id: GO:0005829
    label: cytosol

- description: >-
    Heme-binding function essential for proper folding, PLP binding, and redox regulation
    of CBS activity.
  molecular_function:
    id: GO:0020037
    label: heme binding
  directly_involved_in:
  - id: GO:0019346
    label: transsulfuration
  locations:
  - id: GO:0005829
    label: cytosol

- description: >-
    Allosteric regulation by SAM binding to C-terminal regulatory domain,
    increasing activity 2-3 fold and modulating oligomeric state.
  molecular_function:
    id: GO:1904047
    label: S-adenosyl-L-methionine binding
  directly_involved_in:
  - id: GO:0019346
    label: transsulfuration
  locations:
  - id: GO:0005829
    label: cytosol

proposed_new_terms: []

suggested_questions:
- question: >-
    What is the relative contribution of CBS vs CSE vs 3-MST to tissue-specific
    H2S production in humans?
- question: >-
    What is the physiological relevance of CBS filament formation and does it
    occur in vivo in human tissues?
- question: >-
    How does the interplay between NO/CO/H2S signaling affect CBS activity in
    different cellular contexts?

suggested_experiments:
- description: >-
    Live-cell imaging of CBS oligomeric states using fluorescent protein fusions
    to determine if filamentation occurs physiologically
- description: >-
    Quantitative proteomics to identify CBS protein interaction partners with
    specific biological functions
- description: >-
    Tissue-specific metabolomics in CBS heterozygous carriers to understand
    genotype-phenotype relationships