Bidirectional transsulfuration between homocysteine and cysteine (fungal)

Interconversion of L-homocysteine and L-cysteine through the thioether intermediate L-cystathionine, catalysed by four pyridoxal 5'-phosphate (PLP) dependent enzymes acting in two opposite directions. In the homocysteine-to-cysteine direction, cystathionine beta-synthase condenses L-homocysteine with L-serine to L-cystathionine, and cystathionine gamma-lyase cleaves cystathionine to L-cysteine, 2-oxobutanoate and ammonia; this transfers the sulfur atom of methionine-derived homocysteine onto the serine carbon skeleton and is the only transsulfuration route of mammals. In the cysteine-to-homocysteine direction, cystathionine gamma-synthase condenses L-cysteine with an O-acylated L-homoserine to cystathionine, and cystathionine beta-lyase cleaves cystathionine to L-homocysteine, pyruvate and ammonia; this is the main route to homocysteine in enteric bacteria and plants. Budding yeast and other fungi that assimilate reduced sulfur primarily into the four-carbon chain of homocysteine (by direct sulfhydrylation of O-acetylhomoserine) possess both directions, so they can make cysteine from homocysteine and can also use cysteine as a sole sulfur source for methionine synthesis. Other lineages carry only one direction, and the module is therefore satisfied by either direction or by both.

MODULE:fungal_sulfur_amino_acid_transsulfurationDRAFTMetabolic Pathwaymodules/fungal_sulfur_amino_acid_transsulfuration.yaml
homocysteine metabolic processGO:0050667
YeastPathways:HOMOCYS-CYS-CONVERT
homocysteine and cysteine interconversion (S. cerevisiae, SGD YeastPathways)
Source pathway covering both directions: CYS4 (cystathionine beta-synthase), CYS3 (cystathionine gamma-lyase), STR2 (cystathionine gamma-synthase, RXN-721) and STR3 (cystathionine beta-lyase). All four assignments were retained. YeastCyc calls the cysteine-to-homocysteine direction "forward" and the homocysteine-to-cysteine direction "reverse"; this module names the directions explicitly instead because the literature uses both conventions.
YeastPathways:CYSTEINE-SYN2-PWY
cysteine biosynthesis from homocysteine (S. cerevisiae, SGD YeastPathways)
CYS4 and CYS3; the homocysteine-to-cysteine direction.
YeastPathways:HOMOCYSDEGR-PWY-1
L-cysteine biosynthesis III (from L-homocysteine) (S. cerevisiae, SGD YeastPathways)
Duplicate of CYSTEINE-SYN2-PWY with the same two reactions and catalysts (CYS4, CYS3).
YeastPathways:PWY-821-1
superpathway of sulfur amino acid biosynthesis (S. cerevisiae, SGD YeastPathways)
Superpathway whose transsulfuration reactions (CYS4, CYS3, STR2, STR3) are modelled here. Its sulfate-assimilation reactions (MET3, MET14, MET16, MET10/MET5) belong to aps_dependent_assimilatory_sulfate_reduction; the aspartate-to-homoserine trunk (HOM3, HOM2, HOM6) to aspartate_family_threonine_biosynthesis; homoserine O-acetylation (MET2), O-acetylhomoserine sulfhydrylation (MET17), methionine synthase (MET6) and MET7 folylpolyglutamate synthesis to methionine_biosynthesis; and methionine adenosyltransferase (SAM1, SAM2) to methionine_cycle.
GO:0050667
homocysteine metabolic process
Module-level process. The dedicated term GO:0019346 transsulfuration is obsolete in current GO (GOA rows for CYS4, STR2 and STR3 display it as "obsolete transsulfuration"), so the two directions are instead grounded in GO:0019344 and GO:0071269, both of which are covered by this parent-level concept.
GO:0019344
L-cysteine biosynthetic process
Process for the homocysteine-to-cysteine direction.
GO:0071269
L-homocysteine biosynthetic process
Process for the cysteine-to-homocysteine direction.
PMID:8366024
Cysteine biosynthesis in Saccharomyces cerevisiae occurs through the transsulfuration pathway which has been built up by enzyme recruitment.
Cloning of STR4 (CYS4, cystathionine beta-synthase) and STR1 (CYS3, cystathionine gamma-lyase); fungi possess two operating transsulfuration pathways, whereas mammals have only the homocysteine-to-cysteine route.
Fungi are capable of incorporating reduced sulfur into a four-carbon chain, and they possess two operating transsulfuration pathways. By contrast, synthesis of cysteine from homocysteine is the only existing transsulfuration pathway in mammals.
PMID:10509018
Cysteine biosynthesis in Saccharomyces cerevisiae: a new outlook on pathway and regulation.
cys3 and cys4 disruptants are cysteine-dependent; cysteine is made in yeast exclusively by cystathionine beta-synthase and cystathionine gamma-lyase.
cysteine is synthesized exclusively through the pathway constituted with beta-CTSase and gamma-CTLase
PMID:1577698
Cloning and characterization of the CYS3 (CYI1) gene of Saccharomyces cerevisiae.
CYS3 is the structural gene for cystathionine gamma-lyase; in E. coli it also shows cystathionine gamma-synthase activity with O-succinylhomoserine, illustrating the shared chemistry of the gamma-family enzymes.
CYS3 (CYI1) was concluded to be the structural gene for this enzyme.
PMID:10821189
Cysteine is essential for transcriptional regulation of the sulfur assimilation genes in Saccharomyces cerevisiae.
Disruption of YJR130c (STR2) or YGL184c (STR3) blocks conversion of cysteine into homocysteine, identifying the yeast cysteine-to-homocysteine enzymes.
Two genes that presumably encode cystathionine gamma-synthase and cystathionine beta-lyase were identified by genetic disruption (ORFs YJR130c and YGL184c), yielding yeast strains that cannot convert cysteine into homocysteine.
PMID:22572787
Saccharomyces cerevisiae STR3 and yeast cystathionine β-lyase enzymes: The potential for engineering increased flavor release.
Biochemical characterisation of STR3 as the S. cerevisiae cystathionine beta-lyase.
PMID:11565790
Identification of peroxisomal membrane proteins of Saccharomyces cerevisiae by mass spectrometry.
Peroxisomal proteome supporting the peroxisomal location of STR3 used in the STR3 gene review (IDA in GOA).
PMID:9409150
Metabolism of sulfur amino acids in Saccharomyces cerevisiae.
Review of S. cerevisiae sulfur amino acid metabolism cited by YeastPathways.
7Nodes
4Parts
1Variant Sets
2Variants
4Annotons
2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:fungal_sulfur_amino_acid_transsulfuration deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

8 gene-function check(s) reflected in core functions · 0 conflict(s) · 4 evidence or coverage gap(s) (14 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
cystathionine_beta_synthase_activity CYS4 (Saccharomyces cerevisiae)
UniProtKB:P32582
Family Representative 		cystathionine beta-synthase activity
GO:0004122 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cystathionine_beta_synthase_activity CBS (Homo sapiens)
UniProtKB:P35520
Family Representative 		cystathionine beta-synthase activity
GO:0004122 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cystathionine_gamma_lyase_activity CYS3 (Saccharomyces cerevisiae)
UniProtKB:P31373
Family Representative 		cystathionine gamma-lyase activity
GO:0004123 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cystathionine_gamma_lyase_activity CTH (Homo sapiens)
UniProtKB:P32929
Family Representative 		cystathionine gamma-lyase activity
GO:0004123 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cystathionine_gamma_synthase_activity STR2 (Saccharomyces cerevisiae)
UniProtKB:P47164
Family Representative 		cystathionine gamma-synthase activity
GO:0003962 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cystathionine_gamma_synthase_activity met3 (Schizosaccharomyces pombe)
UniProtKB:O74314
Family Representative 		cystathionine gamma-synthase activity
GO:0003962 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cystathionine_gamma_synthase_activity MetB (Escherichia coli K-12)
UniProtKB:P00935
Family Representative 		cystathionine gamma-synthase activity
GO:0003962 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
cystathionine_beta_lyase_activity STR3 (Saccharomyces cerevisiae)
UniProtKB:P53101
Family Representative 		cysteine-S-conjugate beta-lyase activity
GO:0047804 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cystathionine_beta_lyase_activity cbl1 (Schizosaccharomyces pombe)
UniProtKB:O94350
Family Representative 		cysteine-S-conjugate beta-lyase activity
GO:0047804 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cystathionine_beta_lyase_activity MetC (Escherichia coli K-12)
UniProtKB:P06721
Family Representative 		cysteine-S-conjugate beta-lyase activity
GO:0047804 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
cystathionine_beta_synthase_activity cystathionine beta-synthases
PANTHER:PTHR10314:SF194
Family 		cystathionine beta-synthase activity
GO:0004122 		Family Supported
Family review supports GO:0004122 for PANTHER:PTHR10314:SF194. Canonical serine-dependent CBS activity is placed at the eukaryotic node PTN000034107, inside SF194, which contains the reviewed canonical CBS members. Atypical OAS-dependent MccA in SF242 also carries a CBS name, but its demonstrated OAS/homocysteine chemistry does not by itself establish GO:0004122. SF194 also holds bacterial CysK proteins, which are cysteine synthases rather than canonical CBS and do not receive the PTN000034107 IBA; they are listed as member exceptions. methionine_cycle and fungal_sulfur_amino_acid_transsulfuration select SF194; homocysteine_metabolism selects the base family, which also takes in the cysteine synthases, threonine synthases and desulfhydrases.
cystathionine_gamma_lyase_activity cystathionine gamma-lyases
PANTHER:PTHR11808:SF15
Family 		cystathionine gamma-lyase activity
GO:0004123 		Family Supported
Family review supports GO:0004123 for PANTHER:PTHR11808:SF15. CGL (SF15), as fungal_sulfur_amino_acid_transsulfuration selects; homocysteine_metabolism uses the base family, which also takes in CBL and CGS.
cystathionine_gamma_synthase_activity cystathionine gamma-synthases
Family 		cystathionine gamma-synthase activity
GO:0003962 		Family Id Missing
The family has no identifier linking it to a curated family review.
cystathionine_beta_lyase_activity cystathionine beta-lyases
Family 		cysteine-S-conjugate beta-lyase activity
GO:0047804 		Family Id Missing
The family has no identifier linking it to a curated family review.

Gene-review completeness (8/10 grounded genes reviewed)

6 complete review(s) · 5 with deep research · 2 missing review · 3 reviewed but lacking deep research

Gene Review Complete Deep research
cbl1 O94350 ✓ 10/11 ✗
CBS P35520 ✓ 89/101 ✓
CTH P32929 ✓ ✓ ✗
CYS3 P31373 ✓ ✓ ✓
CYS4 P32582 ✓ ✓ ✓
met3 O74314 ✓ ✓ ✗
MetB (Escherichia coli K-12) P00935 ✗ — —
MetC (Escherichia coli K-12) P06721 ✗ — —
STR2 P47164 ✓ ✓ ✓
STR3 P53101 ✓ ✓ ✓

Details

Bidirectional transsulfuration (homocysteine-cysteine interconversion)Metabolic Pathwayfungal_sulfur_amino_acid_transsulfuration
homocysteine metabolic processGO:0050667

NEW module (2026-10) generalising YeastPathways HOMOCYS-CYS-CONVERT, CYSTEINE-SYN2-PWY, HOMOCYSDEGR-PWY-1 and the transsulfuration part of PWY-821-1. Boundary: from L-homocysteine or L-cysteine to the other via cystathionine. Homoserine O-acetylation (MET2) and direct sulfhydrylation of O-acetylhomoserine (MET17) are kept in methionine_biosynthesis, whose trans-sulfuration route variant uses the same STR2/STR3 (and MetB/MetC) exemplars and GO terms (GO:0003962, GO:0047804) as the cysteine-to-homocysteine variant here; homocysteine remethylation and the human CBS/CTH disease context are in homocysteine_metabolism, whose transsulfuration arm conforms to the homocysteine-to-cysteine variant here. The CBS/CTH-derived hydrogen sulfide production (GO:0070814, for which CYS4 has an IDA) is a side activity outside the module. Generalisation: the module is fungal in scope because only fungi are known to require both directions, but each direction is a variant that also matches the animal (CBS/CTH) or bacterial/plant (CGS/CBL) arm, and the variant set is ONE_OR_MORE. YeastCyc assessment - all four catalysts are correct; the STR2 assignment rests on disruption genetics only (PMID:10821189), STR3 has been assayed (PMID:22572787). CYS3 also shows cystathionine gamma-synthase activity with O-succinylhomoserine when expressed in E. coli (PMID:1577698), but O-succinylhomoserine is absent from yeast and this is not treated as a physiological route. YeastCyc's "forward" (cysteine to homocysteine) and "reverse" (homocysteine to cysteine) labels are the opposite of the convention in the crosswalk rationale (the S. cerevisiae gene reviews follow YeastCyc); directions are named explicitly here. Compartment is asserted per leaf, following the gene reviews: CYS4 and CYS3 cytoplasm, STR2 cytosol, and STR3 peroxisome (Str3p carries a C-terminal PTS1 and was found in the peroxisome proteome, PMID:11565790), so cystathionine produced by STR2 in the cytosol must reach the peroxisome; no module-level compartment is asserted. CYS4 mitochondrial HDA rows in GOA are not used. GO-CAM comparison - the four YeastPathways models agree with the module on genes and functions but have no causal edges, place STR3 in the cytosol rather than the peroxisome, and CYSTEINE-SYN2-PWY uses cytoplasm where the others use cytosol. In the PomBase model 66a3e0bb00001342 the S. pombe met3 cystathionine gamma-synthase activity is placed part_of GO:0019344 L-cysteine biosynthetic process, although this reaction consumes cysteine and leads to homocysteine (GO:0071269 would fit), and a cystathionine beta-synthase activity is enabled only by a placeholder protein (see knowledge gap). GO:0019346 transsulfuration is obsolete in current GO, so it is not used as a concept.

Variant set: Direction of sulfur transfer by metabolic direction / lineage (One Or More)

Not mutually exclusive: S. cerevisiae carries both directions, mammals only homocysteine-to-cysteine, and enteric bacteria, plants and S. pombe (on current gene evidence) only cysteine-to-homocysteine.

Homocysteine to cysteine (cystathionine beta-synthase + gamma-lyase)Metabolic Pathwayhomocysteine_to_cysteine_route

Moves the sulfur of homocysteine onto the serine skeleton to make cysteine. In S. cerevisiae this is the only route to cysteine (cys3 and cys4 disruptants are cysteine auxotrophs); the animal CBS/CTH pathway is the same chemistry.

L-cysteine biosynthetic processGO:0019344

Connections

cbs_step -> cgl_step Precedes
Cystathionine beta-synthase supplies cystathionine to the gamma-lyase.
Part 1: cystathionine formation from homocysteine and serine
Cystathionine beta-synthaseReactioncbs_step

Annotons

Cystathionine beta-synthase
cystathionine_beta_synthase_activity
Participant: Family: cystathionine beta-synthases
Family:
cystathionine beta-synthasesPANTHER:PTHR10314:SF194
Representative Members: CYS4 (Saccharomyces cerevisiae)UniProtKB:P32582 CBS (Homo sapiens)UniProtKB:P35520
Required Function:
cystathionine beta-synthase activityGO:0004122
Grounded on subfamily PTHR10314:SF194; the parent family PTHR10314 also contains O-acetylserine sulfhydrylases (cysteine synthases).

Function

cystathionine beta-synthase activityGO:0004122
Substrates: L-homocysteine L-serine
Products: L-cystathionine water

Locations

cytoplasmGO:0005737

PLP-dependent beta-replacement condensing homocysteine with serine to cystathionine.

Part 2: cystathionine cleavage to cysteine
Cystathionine gamma-lyaseReactioncgl_step

Annotons

Cystathionine gamma-lyase
cystathionine_gamma_lyase_activity
Participant: Family: cystathionine gamma-lyases
Family:
cystathionine gamma-lyasesPANTHER:PTHR11808:SF15
Representative Members: CYS3 (Saccharomyces cerevisiae)UniProtKB:P31373 CTH (Homo sapiens)UniProtKB:P32929
Required Function:
cystathionine gamma-lyase activityGO:0004123

Function

cystathionine gamma-lyase activityGO:0004123
Substrates: L-cystathionine water
Products: L-cysteine 2-oxobutanoate ammonia

Locations

cytoplasmGO:0005737

PLP-dependent alpha,gamma-elimination releasing cysteine from cystathionine.

Cysteine to homocysteine (cystathionine gamma-synthase + beta-lyase)Metabolic Pathwaycysteine_to_homocysteine_route

Moves the sulfur of cysteine onto the four-carbon homoserine skeleton to make homocysteine, allowing cysteine to serve as a sulfur source for methionine. The same two-enzyme arm is the trans-sulfuration route of methionine_biosynthesis; it is repeated here so that the interconversion can be represented as a whole, and both modules use the same exemplars and GO terms.

L-homocysteine biosynthetic processGO:0071269

Connections

cgs_step -> cbl_step Precedes
Cystathionine gamma-synthase supplies cystathionine to the beta-lyase.
Part 1: cystathionine formation from cysteine and O-acylhomoserine
Cystathionine gamma-synthaseReactioncgs_step

Annotons

Cystathionine gamma-synthase
cystathionine_gamma_synthase_activity
Participant: Family: cystathionine gamma-synthases
Family:
cystathionine gamma-synthases
Representative Members: STR2 (Saccharomyces cerevisiae)UniProtKB:P47164 met3 (Schizosaccharomyces pombe)UniProtKB:O74314 MetB (Escherichia coli K-12)UniProtKB:P00935
Required Function:
cystathionine gamma-synthase activityGO:0003962
No PANTHER family is asserted: the fungal enzymes (STR2, S. pombe met3) are in PTHR42699 whereas E. coli MetB is in PTHR11808:SF75, and PTHR11808 as a whole also contains lyases and sulfhydrylases.

Function

cystathionine gamma-synthase activityGO:0003962
Substrates: L-cysteine O-acetyl-L-homoserine (fungi) or O-succinyl-L-homoserine (enterobacteria)
Products: L-cystathionine acetate or succinate

Locations

cytosolGO:0005829

PLP-dependent gamma-replacement condensing cysteine with an O-acylhomoserine to cystathionine.

Part 2: cystathionine cleavage to homocysteine
Cystathionine beta-lyaseReactioncbl_step

Annotons

Cystathionine beta-lyase
cystathionine_beta_lyase_activity
Participant: Family: cystathionine beta-lyases
Family:
cystathionine beta-lyases
Representative Members: STR3 (Saccharomyces cerevisiae)UniProtKB:P53101 cbl1 (Schizosaccharomyces pombe)UniProtKB:O94350 MetC (Escherichia coli K-12)UniProtKB:P06721
Required Function:
cysteine-S-conjugate beta-lyase activityGO:0047804
No PANTHER family is asserted: STR3 and S. pombe cbl1 are PTHR11808:SF50, whereas E. coli MetC is in a separate family, PTHR43500.

Function

cysteine-S-conjugate beta-lyase activityGO:0047804 Cystathionine beta-lyase activity. The dedicated GO term GO:0004121 is obsolete and was merged into GO:0047804, of which L-cystathionine is the physiological S-substituted cysteine substrate here.
Substrates: L-cystathionine water
Products: L-homocysteine pyruvate ammonium

Locations

peroxisomeGO:0005777

PLP-dependent alpha,beta-elimination releasing homocysteine from cystathionine.