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 30 characterized proteins
cysK: O-acetylserine sulfhydrylase
SST: serine O-succinyltransferase
CBS: cystathionine beta-synthase
CGL: cystathionine gamma-lyase
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] adenylyltransferase/sulfurtransferase
- 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
serK: serine kinase (ADP-dependent)
- UniProt sequence Q5JD03: RecName: Full=L-serine kinase SerK {ECO:0000305}; EC=2.7.1.226 {ECO:0000269|PubMed:27857065, ECO:0000269|PubMed:28358477};
- Total: 1 characterized proteins
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};
- Ignore hits to Q4JDI4 when looking for 'other' hits (phosphoglycerate dehydrogenase (EC 1.1.1.95))
- 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.
- Total: 1 HMMs and 20 characterized proteins
serC: 3-phosphoserine aminotransferase
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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 the paper from 2019 on GapMind for amino acid biosynthesis, the paper from 2022 on GapMind for carbon sources, or view the source code, or see changes to Amino acid biosynthesis since the publication.
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