Definition of L-serine biosynthesis
As rules and steps, or see full text
Rules
Overview: Serine biosynthesis in GapMind is based on MetaCyc pathway L-serine biosynthesis I (link). Pathway II (link) is not included because it is known only in plants. Also, MetaCyc states that the gene for the first step (EC 3.1.3.38) is not known. (Alkaline phosphatase from E. coli (phoA) is reported to be catalyze this reaction, but it has rather broad specificity.)
Steps
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
serB: phosphoserine phosphatase
- Curated proteins or TIGRFams with EC 3.1.3.3
- Ignore hits to items matching EC 1.1.1.95 when looking for 'other' hits
- Ignore hits to P60487 when looking for 'other' hits (pyridoxal phosphatase (EC 3.1.3.74). Chronophin; Pyridoxal 5'-phosphate phosphatase; Pyridoxal phosphate phosphatase; PLP phosphatase; EC 3.1.3.16; EC 3.1.3.74)
- Ignore hits to Q96GD0 when looking for 'other' hits (pyridoxal phosphatase (EC 3.1.3.74). Chronophin; Pyridoxal phosphate phosphatase; PLP phosphatase; EC 3.1.3.16; EC 3.1.3.74)
- Ignore hits to Q9P376 when looking for 'other' hits (CTD phosphatase Fcp1; EC 3.1.3.3. RNA polymerase II subunit A C-terminal domain phosphatase; CTD phosphatase fcp1; EC 3.1.3.16)
- Ignore hits to O07014 when looking for 'other' hits (phosphoserine phosphatase (EC 3.1.3.3))
- Ignore hits to Q3ZBF9 when looking for 'other' hits (Chronophin; Protein serine phosphatase; Pyridoxal phosphate phosphatase; PLP phosphatase; EC 3.1.3.16; EC 3.1.3.74)
- Ignore hits to P00634 when looking for 'other' hits (alkaline phosphatase (EC 3.1.3.1). alkaline phosphatase (EC 3.1.3.1; EC 3.1.3.75; EC 3.1.3.41; EC 3.1.3.74; EC 3.1.3.99; EC 3.1.3.5; EC 3.1.3.6; EC 3.1.3.89; EC 3.1.3.91; EC 3.1.3.60; EC 3.1.3.15; EC 3.1.3.102; EC 3.1.3.108; EC 3.1.3.11; EC 3.1.3.20; EC 3.1.3.19; EC 3.1.3.3; EC 3.6.1.25; EC 3.6.1.1; EC 3.1.3.23; EC 3.1.3.38; EC 3.1.3.18; EC 3.1.3.68; EC 3.9.1.1). alkaline phosphatase (EC 3.1.3.1; EC 3.1.3.75; EC 3.1.3.41; EC 3.1.3.74; EC 3.1.3.99; EC 3.1.3.5; EC 3.1.3.6; EC 3.1.3.89; EC 3.1.3.91; EC 3.1.3.60; EC 3.1.3.15; EC 3.1.3.102; EC 3.1.3.108; EC 3.1.3.11; EC 3.1.3.20; EC 3.1.3.19; EC 3.1.3.3; EC 3.6.1.25; EC 3.6.1.1; EC 3.1.3.23; EC 3.1.3.38; EC 3.1.3.18; EC 3.1.3.68; EC 3.9.1.1))
- Ignore hits to P0AE22 when looking for 'other' hits (acid phosphatase (EC 3.1.3.2). class B acid phosphatase; EC 3.1.3.2. Class B acid phosphatase; CBAP; EC 3.1.3.2. acid phosphatase / phosphotransferase (EC 3.1.3.2; EC 3.1.3.31; EC 3.1.3.5; EC 3.1.3.6; EC 3.1.3.89; EC 3.1.3.34; EC 3.1.3.3). acid phosphatase / phosphotransferase (EC 3.1.3.2; EC 3.1.3.5; EC 3.1.3.6; EC 3.1.3.89; EC 3.1.3.34; EC 3.1.3.3))
- Ignore hits to P17906 when looking for 'other' hits (phosphoserine phosphatase (EC 3.1.3.3). Phosphoserine phosphatase RsbX; Sigma-B negative effector; EC 3.1.3.3)
- Ignore hits to P40399 when looking for 'other' hits (phosphoserine phosphatase (EC 3.1.3.3). Phosphoserine phosphatase RsbU; Sigma factor SigB regulation protein RsbU; EC 3.1.3.3)
- Ignore hits to P94526 when looking for 'other' hits (Sugar-phosphatase AraL; Arabinose operon protein AraL; Phosphoserine phosphatase; EC 3.1.3.23; EC 3.1.3.3)
- Ignore hits to D3DFP8 when looking for 'other' hits (Putative phosphoserine phosphatase 2; PSP 2; PSPase 2; Metal-independent phosphoserine phosphatase 2; iPSP2; O-phosphoserine phosphohydrolase 2; EC 3.1.3.3. phosphoserine phosphatase (EC 3.1.3.3))
- UniProt sequence Q9K8N3: SubName: Full=BH2972 protein {ECO:0000313|EMBL:BAB06691.1};
- UniProt sequence A0A1R2PVY2: RecName: Full=Phosphoserine phosphatase {ECO:0000256|ARBA:ARBA00015196}; EC=3.1.3.3 {ECO:0000256|ARBA:ARBA00012640}; AltName: Full=O-phosphoserine phosphohydrolase {ECO:0000256|ARBA:ARBA00031693};
- UniProt sequence N9V397: SubName: Full=Phosphoglycerate mutase family protein, putative {ECO:0000313|EMBL:ENY63406.1};
- Predicted: UniProt sequence A0A6B4WGC7: SubName: Full=DUF1015 domain-containing protein {ECO:0000313|EMBL:MBD5586605.1};
- UniProt sequence P72649: SubName: Full=Phosphoglycerate mutase {ECO:0000313|EMBL:BAA16651.1};
- UniProt sequence A0A3D8VK77: SubName: Full=Histidine phosphatase family protein {ECO:0000313|EMBL:RDY69752.1};
- UniProt sequence A0A0H2XA29: SubName: Full=Phosphoglycerate mutase {ECO:0000313|EMBL:AAY50331.1};
- UniProt sequence F9VNX9: SubName: Full=Phosphoserine aminotransferase {ECO:0000313|EMBL:BAK54487.1}; EC=2.6.1.52 {ECO:0000313|EMBL:BAK54487.1};
- Comment: CA265_RS22635 (see Fitness Browser) is diverged serB and is auxotrophic. It also appears to be fused to diverged serA, but there is another serA in the genome (CA265_RS09010), so CA265_RS22635 may not be a functional dehydrogenase. Echvi_2777 (see Fitness Browser) from Echinicola vietnamensis KMM 6221 is a diverged serB and is auxotrophic, rescued by serine. It is fused to serA and probably provides that activity as well. Hits to serA are ignored because of serAB fusions. Some curated resources link this EC number to protein phosphatases, or to non-specific periplasmic phosphatases, that are unlikely to play a role in serine biosynthesis. These are all marked ignore (P60487, Q96GD0, Q3ZBF9, P00634, P0AE22, Q9P376, O07014). Similarly, Swiss-Prot annotates RsbX (P17906) and RsbU (P40399) with this EC number, but they probably act on proteins. And, AraL (P94526) is ignored because although it does have activity on phosphoserine, it is a promiscuous phosphatase (supplementary material of PMC4413258). Hydrogenobacter thermophilus (D3DFP8) has an unusual enzyme with both a homodimeric form (PspA) and a heterodimeric form (PspA-PspB) (PMID:22337887). PspB could not be purified on its own and the heteromeric form has lower activity than PspA, so it is not clear if PspB is active; thus PspB (D3DFP8) is ignored. PMID:25848029 shows that BH2972 (Q9K8N3) and X3MFA4 (now A0A1R2PVY2) have this activity. 5zr2C (N9V397) is serB in Entamoeba histolytica (see PMID:30935984) In Clostridiodes difficile, the serine synthesis operon includes CDIF630erm_01132 (A0A6B4WGC7), a DUF1015 protein which is speculated to replace serB (PMC6110889). This subfamily is usually colocated with serA or serC3 (see neighbors of ADT23_RS05570 or A0A6B4WGC7), and is structurally related to the N-terminal domain of serine kinases (using foldseek). Furthermore, genomes that encode this subfamily usually lack any known form of serB. The phosphoserine phosphatase from Synechocystis PCC 6803 (Slr1124, P72649) was confirmed by biochemical experiments (PMID:25701735). Similar proteins from Lysobacter OAE881 or Xanthomonas campestris 8004 (45% or 39% identity; GGC55_RS00335 = A0A3D8VK77 and Xcc-8004.4079.1 = A0A0H2XA29) are essential, and close homologs thereof are encoded adjacent to serA, so these must also be serB. ST1217 (F9VNX9) was shown to be a phosphoserine phosphatase (PMID:18054776).
- Total: 2 HMMs and 37 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