Definition of L-cysteine biosynthesis
As rules and steps, or see full text
Rules
Overview: Cysteine biosynthesis in GapMind is based on MetaCyc pathways L-cysteine biosynthesis I from serine and sulfide (link), II (tRNA-dependent) (link), III from serine and homocysteine (link), V (protein-bound thiocarboxylates) (link), VIII via serine kinase (link), or IX via phosphoserine (link). There is no pathway IV. Pathway VI (from serine + methionine) is not included because it is not found in prototrophic bacteria. (It is found in H. pylori, which lacks biosynthesis of homocysteine or methionine; also, it is a supserset of the reactions in pathway III, from serine and homocysteine.) Pathway VII is not included because it requires sulfocysteine, an uncommon precursor. GapMind also describes cysteine biosynthesis with O-succinylserine as an intermediate (PMID:28581482), instead of O-acetylserine (as in pathway I).
- all:
- from-serine
- or serA, serC and from-phosphoserine
- or from-serine-homocysteine
- from-phosphoserine:
- sepS and pscS
- or cysO, moeZ, Mt_cysM and mec
- or PSSH
- Comment: Phosphoserine can be converted to cysteine by the tRNA-dependent pathway II (sepS and pscS), the protein-bound thiocarboxylate pathway V with the carrier protein cysO, or by direct sulfhydrylation (PSSH) as in pathway IX.
- from-serine-homocysteine: CBS and CGL
- Comment: In many organisms, the sulfhydryl group of cysteine is used to form homocysteine and methionine, but this pathway can also run in reverse. GapMind uses a pathway requirement to warn if an organism is modeled as synthesizing methionine and cysteine from each other.
- from-serine:
- cysE and cysK
- or SST and cysK
- or serK and PSSH
- Comment: Cysteine can be formed from serine via O-acetylserine as in pathway I (cysE and cysK), via O-succinylserine (SST), or via serine kinase (serK) as in pathway IX. For the O-succinylserine pathway, the identity of the O-succinylserine sulfhydrylase is not proven, but it is expected to be similar to cysK.
Steps
cysE: serine acetyltransferase
- Curated proteins or TIGRFams with EC 2.3.1.30
- UniProt sequence Q72EB6_DESVH: RecName: Full=serine O-acetyltransferase {ECO:0000256|ARBA:ARBA00013266}; EC=2.3.1.30 {ECO:0000256|ARBA:ARBA00013266};
- UniProt sequence B8DIT5_DESVM: RecName: Full=serine O-acetyltransferase {ECO:0000256|ARBA:ARBA00013266}; EC=2.3.1.30 {ECO:0000256|ARBA:ARBA00013266};
- Comment: Desulfovibrios have a somewhat diverged serine O-acetyltransferase. DVU0662 (Q72EB6_DESVH) and DvMF_2657 (B8DIT5_DESVM) are both essential which suggests that they are correctly annotated.
- Total: 1 HMMs and 33 characterized proteins
cysK: O-acetylserine or O-succinylserine sulfhydrylase
- Curated proteins or TIGRFams with EC 2.5.1.47
- Ignore hits to O22682 when looking for 'other' hits (cysteine synthase (EC 2.5.1.47). S-sulfo-L-cysteine synthase (O-acetyl-L-serine-dependent), chloroplastic; AtCS26; Beta-substituted Ala synthase 5;1; ARAth-Bsas5;1; O-acetylserine sulfhydrylase; EC 2.5.1.144. S-sulfocysteine synthase (EC 2.5.1.144))
- Ignore hits to Q9YBL2 when looking for 'other' hits (cysteine synthase (EC 2.5.1.47); O-phosphoserine sulfhydrylase (EC 2.5.1.65). Protein CysO; Cystathionine beta-synthase; Cysteine synthase; O-acetylserine sulfhydrylase; O-phosphoserine sulfhydrylase; Serine sulfhydrase; EC 4.2.1.22; EC 2.5.1.47; EC 2.5.1.65. O-phosphoserine sulfhydrylase monomer (EC 2.5.1.65))
- Ignore hits to CH_123612 when looking for 'other' hits (O-acetylhomoserine O-acetylserine sulphydrylase)
- Comment: E. coli also has cysM (same EC number). BRENDA misannotates O22682 and Q9YBL2 with this activity. CH_123612 maybe have this activity but is annotated more vaguely.
- Total: 3 HMMs and 57 characterized proteins
SST: serine O-succinyltransferase
CBS: cystathionine beta-synthase
- Curated proteins or TIGRFams with EC 4.2.1.22
- Ignore hits to Q3TWN3 when looking for 'other' hits (cystathionine beta-synthase (EC 4.2.1.22). Metal transporter CNNM2; Ancient conserved domain-containing protein 2; mACDP2; Cyclin-M2)
- Ignore hits to Q5SK23 when looking for 'other' hits (cystathionine beta-synthase (EC 4.2.1.22))
- Ignore hits to Q9EYM7 when looking for 'other' hits (cysteine-S-conjugate beta-lyase (EC 4.4.1.13))
- Ignore hits to HS04050-MONOMER when looking for 'other' hits (cystathionine gamma-lyase (EC 4.4.1.1). Cystathionine gamma-lyase; CGL; CSE; Cysteine desulfhydrase; Cysteine-protein sulfhydrase; Gamma-cystathionase; Homocysteine desulfhydrase; EC 4.4.1.1; EC 4.4.1.2. cystathionine γ-lyase monomer (EC 4.4.1.1; EC 4.4.1.2; EC 4.2.1.22))
- Comment: Q3TWN3 and Q5SK23 are misannotated in BRENDA. Q9EYM7 may well have this activity (PMID:12101301). Human CGL is given this EC number as well by metacyc (link), but is not expected to form cystathionine from serine + homocysteine.
- Total: 1 HMMs and 13 characterized proteins
CGL: cystathionine gamma-lyase
- Curated proteins matching cystathionine gamma-lyase
- Curated proteins matching cystathionine-gamma-lyase
- Ignore hits to Q9M1R1 when looking for 'other' hits (cystathionine gamma-lyase (EC 4.4.1.1). L-cysteine desulfhydrase; AtL-CDes1; L-CDes1; AtLCD; EC 4.4.1.28)
- Ignore hits to F4K5T2 when looking for 'other' hits (L-cysteine desulfidase (EC 4.4.1.28). Bifunctional cystathionine gamma-lyase/cysteine synthase; Beta-substituted Ala synthase 4;3; ARAth-Bsas4;3; L-cysteine desulfhydrase 1; DES1; O-acetylserine (thiol)-lyase; OASTL; Protein CS-LIKE; EC 2.5.1.47; EC 4.4.1.1)
- Ignore hits to Q1M0P5 when looking for 'other' hits (Cystathionine gamma-synthase; CGS; O-succinylhomoserine (thiol)-lyase; EC 2.5.1.48. cystathionine gamma-synthase (EC 2.5.1.48))
- Ignore hits to CH_088676 when looking for 'other' hits (cystathionine beta-lyase; EC 4.4.1.8)
- Comment: EC 4.4.1.1 includes some other reactions, so it is not used to define CGL. Q9M1R1 is misannotated in BRENDA. SwissProt annotates the cysteine desulfurase DES1 (F4K5T2) with this activity, but we did not find evidence for it, so it is ignored. "MetB" from Helicobacter pylori was originally reported to be a cystathionine gamma-synthase (i.e., Q1M0P5 in BRENDA), but was later identified as a CGL (PMC2820867), so Q1M0P5 is ignored. Similarly, "MetC" from Lactoccus lactis (A2RM21) is reported to be a CGL and a cystathionine beta-lyase (PMID:10620674); another paper proposed that it is a CBL but did not distinguish between the two activities (PMC91783, cited by CharProtDB, which is ignored).
- Total: 17 characterized proteins
sepS: O-phosphoseryl-tRNA ligase
pscS: Sep-tRNA:Cys-tRNA synthase
Mt_cysM: CysO-thiocarboxylate-dependent cysteine synthase
mec: [CysO sulfur-carrier protein]-S-L-cysteine hydrolase
moeZ: [sulfur carrier protein CysO]--sulfur ligase
- Curated sequence G185E-7476-MONOMER: Probable adenylyltransferase/sulfurtransferase MoeZ; EC 2.7.7.-; EC 2.8.1.-. [sulfur-carrier protein CysO]--sulfur ligase
- Ignore hits to MONOMER-21317 when looking for 'other' hits ([sulfur-carrier protein]--sulfur ligase)
- Comment: A0A2R3ZBG9 (link) is not reported to be involved in cysteine biosynthesis, but it has a similar chemical activity, so similarity to it is ignored.
- Total: 1 characterized proteins
cysO: sulfur carrier protein CysO
- Curated sequence P9WP33: Sulfur carrier protein CysO; 9.5 kDa culture filtrate antigen cfp10A. CysO sulfur-carrier protein
- Total: 1 characterized proteins
PSSH: O-phosphoserine sulfhydrylase
- Curated proteins or TIGRFams with EC 2.5.1.65
- Ignore hits to P9WP53 when looking for 'other' hits ([CysO sulfur-carrier protein]-thiocarboxylate-dependent cysteine synthase (EC 2.5.1.113); O-phosphoserine sulfhydrylase (EC 2.5.1.65). O-phosphoserine sulfhydrylase; OPS sulfhydrylase; CysO-thiocarboxylate-dependent cysteine synthase; Cysteine synthase B; CSase B; O-phosphoserine-specific cysteine synthase; [CysO sulfur-carrier protein]-thiocarboxylate-dependent cysteine synthase; EC 2.5.1.113. CysO-thiocarboxylate-dependent cysteine synthase monomer (EC 2.5.1.113))
- Ignore hits to A2GMG5 when looking for 'other' hits (cysteine synthase (EC 2.5.1.47))
- Comment: BRENDA misannotates Mt_cysM (P9WP53) as this. Trichomonas cysteine synthase (A2GMG5) probably has this activity as well, so similarity to it is ignored.
- Total: 4 characterized proteins
serK: serine kinase (ADP-dependent)
serA: 3-phosphoglycerate dehydrogenase
- Curated proteins or TIGRFams with EC 1.1.1.95
- UniProt sequence A0A1X9ZCD3: SubName: Full=3-phosphoglycerate dehydrogenase {ECO:0000313|EMBL:ARS42937.1};
- UniProt sequence Q6LWW6: RecName: Full=D-3-phosphoglycerate dehydrogenase {ECO:0000256|RuleBase:RU363003}; EC=1.1.1.95 {ECO:0000256|RuleBase:RU363003};
- Ignore hits to Q4JDI4 when looking for 'other' hits (phosphoglycerate kinase (EC 2.7.2.3))
- Ignore hits to HP_RS05420-MONOMER when looking for 'other' hits (cinnamyl-alcohol dehydrogenase (EC 1.1.1.2; EC 1.1.1.95; EC 1.1.1.195))
- Ignore hits to SGL_RS08600-MONOMER when looking for 'other' hits (glycerate dehydrogenase (EC 1.1.1.29))
- Predicted: UniProt sequence A0A374I5P9: RecName: Full=D-3-phosphoglycerate dehydrogenase {ECO:0000256|ARBA:ARBA00021582}; EC=1.1.1.399 {ECO:0000256|ARBA:ARBA00013001}; EC=1.1.1.95 {ECO:0000256|ARBA:ARBA00013143}; AltName: Full=2-oxoglutarate reductase {ECO:0000256|ARBA:ARBA00030455};
- UniProt sequence Q5JGC4: SubName: Full=D-3-phosphoglycerate dehydrogenase {ECO:0000313|EMBL:BAD86155.1};
- Comment: BRENDA::Q4JDI4 is misannotated as 3-phosphoglycerate dehydrogenase instead of 3-phosphoglycerate kinase. (The curators were notified and report that they have corrected this.) CA265_RS09010 (A0A1X9ZCD3) from Pedobacter sp. GW460-11-11-14-LB5 is annotated as 3-phosphoglycerate dehydrogenase and has auxotrophic phenotypes. In particular, mutants are partially rescued by glycine or serine. Also it is adjacent to the putative serC. MMP1588 (Q6LWW6) was identified as the serA of Methanococcus (PMC1797378). Ignore link_RS05420-MONOMER which has this EC but has a different function. Ignore similarity to sll1908 (link_RS08600-MONOMER) which seems likely to be serA but was proposed (without experimental evidence) to be hydroxpyruvate reductase. In Roseburia faecis, the putative serA (A0A374I5P9) is diverged but is similar to the serA part of Echvi_2777 and is conserved next to serC and DUF1015 (putative serB). In Thermococcus kodakarensis, TK1966 (Q5JGC4) is the 3-phosphoglycerate dehydrogenase (PMC5120207).
- Total: 1 HMMs and 30 characterized proteins
serC: 3-phosphoserine aminotransferase
- Curated proteins or TIGRFams with EC 2.6.1.52
- UniProt sequence Y959_METJA: RecName: Full=Uncharacterized aminotransferase MJ0959; EC=2.6.1.-;
- UniProt sequence Q2FXK2: RecName: Full=Aminotransferase class V domain-containing protein {ECO:0000259|Pfam:PF00266};
- Predicted: UniProt sequence A5I0W7: SubName: Full=Serine--glyoxylate aminotransferase {ECO:0000313|EMBL:CAL82678.1}; EC=2.6.1.45 {ECO:0000313|EMBL:CAL82678.1};
- Predicted: UniProt sequence A0A843E9R6: SubName: Full=Alanine--glyoxylate aminotransferase family protein {ECO:0000313|EMBL:MBO5653953.1};
- Predicted: UniProt sequence A0A1T4W7T3: SubName: Full=Aspartate aminotransferase {ECO:0000313|EMBL:SKA73374.1};
- Predicted: UniProt sequence A0A097AUI2: SubName: Full=Serine-pyruvate aminotransferase {ECO:0000313|EMBL:AIS53461.1}; EC=2.6.1.51 {ECO:0000313|EMBL:AIS53461.1};
- Comment: MJ0959 (Y959_METJA) is phosphoserine transaminase (PMID:17071763). A mutant in the putative aminotransferase SAUSA300_1669 = Q2FXK2 is a serine auxotroph (PMC5912478), and this gene is conserved near other serine synthesis genes (SerC2 in PMC9026213). A5I0W7 is a putative aminotransferase and is conserved near serine synthesis genes (SerC3 in PMC9026213; also see CDIF630erm_01130 in PMC6110889). Some moderately diverged SerC3 homologs are also conserved near serine synthesis genes (A3204_00420, similar to A0A843E9R6; G452_RS0102660, similar to A0A1T4W7T3). In Thermoanaerobacter kivui LKT-1, a putative transaminase (TKV_RS11400, A0A097AUI2) is encoded next to serA; by homology, it might be a serine:pyruvate aminotransferase or a phosphoserine transaminase; given the conserved proximity to serA, we predicted that it is serC.
- Total: 3 HMMs and 20 characterized proteins
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About GapMind
Each pathway is defined by a set of rules based on individual steps or genes. Candidates for each step are identified by using
ublast (a fast alternative to protein BLAST)
against a database of manually-curated proteins (most of which are experimentally characterized) or by using
HMMer with enzyme models (usually from
TIGRFam). Ublast hits may be split across two different proteins.
A candidate for a step is "high confidence" if either:
- ublast finds a hit to a characterized protein at above 40% identity and 80% coverage, and bits >= other bits+10.
- (Hits to curated proteins without experimental data as to their function are never considered high confidence.)
- HMMer finds a hit with 80% coverage of the model, and either other identity < 40 or other coverage < 0.75.
where "other" refers to the best ublast hit to a sequence that is not annotated as performing this step (and is not "ignored").
Otherwise, a candidate is "medium confidence" if either:
- ublast finds a hit at above 40% identity and 70% coverage (ignoring otherBits).
- ublast finds a hit at above 30% identity and 80% coverage, and bits >= other bits.
- HMMer finds a hit (regardless of coverage or other bits).
Other blast hits with at least 50% coverage are "low confidence."
Steps with no high- or medium-confidence candidates may be considered "gaps."
For the typical bacterium that can make all 20 amino acids, there are 1-2 gaps in amino acid biosynthesis pathways.
For diverse bacteria and archaea that can utilize a carbon source, there is a complete
high-confidence catabolic pathway (including a transporter) just 38% of the time, and
there is a complete medium-confidence pathway 63% of the time.
Gaps may be due to:
- our ignorance of proteins' functions,
- omissions in the gene models,
- frame-shift errors in the genome sequence, or
- the organism lacks the pathway.
GapMind relies on the predicted proteins in the genome and does not search the six-frame translation. In most cases, you can search the six-frame translation by clicking on links to Curated BLAST for each step definition (in the per-step page).
For more information, see:
If you notice any errors or omissions in the step descriptions, or any questionable results, please let us know
by Morgan Price, Arkin group, Lawrence Berkeley National Laboratory