Definition of glycine biosynthesis
As rules and steps, or see full text
Rules
Overview: Glycine biosynthesis in GapMind is based on MetaCyc pathways glycine biosynthesis I from serine (link), III from glyoxylate (link), or IV from threonine (link). Pathway II from methylene-tetrahydrofolate, CO2, and ammonia (link) is not included because it is not clear that bacteria really run this in reverse (although apparently budding yeast can). Glcyine synthiesis by glyXL/glyXS, whose biochemical function is not known, is also represented. Another pathway not listed is the formation of glycine from glycolate as in Pelagibacter (see PMID:23096402). This is an unusual nutritional requirement.
- all:
- from_serine
- or via_glyoxylate
- or from_threonine
- or glyXL and glyXS
- from_threonine: gly1
- via_glyoxylate: aceA and agx1
- Comment: For biosynthesis from glyoyxlate (pathway III), assume that the glyoxylate is formed from isocitrate (an intermediate in the TCA cycle).
- from_serine: glyA
Steps
glyA: serine hydroxymethyltransferase
- Curated proteins or TIGRFams with EC 2.1.2.1
- Curated proteins matching Serine hydroxymethyltransferase
- Comment: Some methanogens use tetrahydromethanopterin instead of tetrahydrofolate as the folate carrier, which is annotated as "Serine hydroxymethyltransferase" but with a different EC number.
- Total: 52 characterized proteins
aceA: isocitrate lyase
- Curated proteins or TIGRFams with EC 4.1.3.1
- Curated sequence CH_123497: Isocitrate lyase
- Ignore hits to Q05957 when looking for 'other' hits (isocitrate lyase (EC 4.1.3.1). Petal death protein; (R)-2-methylmalate lyase; D-citramalate lyase; Oxalacetic hydrolase; PSR132; EC 3.7.1.1; EC 4.1.3.-)
- Ignore hits to P28467 when looking for 'other' hits (Isocitrate lyase; ICL; Isocitrase; Isocitratase; EC 4.1.3.1. isocitrate lyase; EC 4.1.3.1)
- Comment: CH_123497 is isocitrate lyase but is annotated without the EC number. Q05957 is misannotated in BRENDA as this function; it prefers other substrates (PMID:16342929) P28467 is annotated as this by two resources but is only 15 amino acids, so it is ignored.
- Total: 1 HMMs and 35 characterized proteins
agx1: alanine--glyoxylate aminotransferase
- Curated proteins or TIGRFams with EC 2.6.1.44
- Ignore hits to P84188 when looking for 'other' hits (Serine--glyoxylate aminotransferase; SGAT; Alanine--glyoxylate aminotransferase; AGT; EC 2.6.1.45; EC 2.6.1.44)
- Ignore hits to P84187 when looking for 'other' hits (Serine--glyoxylate aminotransferase; SGAT; Alanine--glyoxylate aminotransferase; AGT; EC 2.6.1.45; EC 2.6.1.44)
- Comment: P84188 and P84187 are ignored because they appear to be sequence fragments and do not contain the full aminotransferase domain
- Total: 21 characterized proteins
gly1: L-threonine aldolase
- Curated proteins or TIGRFams with EC 4.1.2.5
- Curated proteins or TIGRFams with EC 4.1.2.48
- Ignore hits to P0A825 when looking for 'other' hits (low-specificity L-threonine aldolase (EC 4.1.2.48). serine hydroxymethyltransferase; EC 2.1.2.1. Serine hydroxymethyltransferase; SHMT; Serine methylase; EC 2.1.2.1. serine hydroxymethyltransferase (EC 2.1.2.1). serine hydroxymethyltransferase (EC 2.1.2.1))
- Curated sequence CH_123166: L-threonine aldolase
- Ignore hits to O07051 when looking for 'other' hits (L-allo-threonine aldolase (EC 4.1.2.49). L-allo-threonine aldolase; EC 4.1.2.-. L-allo-threonine aldolase; L-allo-TA; L-allo-threonine acetaldehyde-lyase; EC 4.1.2.49. L-allo-threonine aldolase subunit (EC 4.1.2.48))
- Comment: E. coli serA (P0A825) is annotated in BRENDA as threonine aldolase, but other resources report that it is active on allothreonine only. CH_123166 is L-threonine aldolase but was annotated without the EC number, so it is added manually. O07051 is ignored because it specific for L-allothreonine.
- Total: 14 characterized proteins
glyXL: putative glycine synthesis enzyme, catalytic component
- UniProt sequence Q8G510: RecName: Full=UPF0210 protein BL1209 {ECO:0000255|HAMAP-Rule:MF_01221};
- UniProt sequence Q6LXC5: RecName: Full=UPF0210 protein MMP1427 {ECO:0000255|HAMAP-Rule:MF_01221};
- UniProt sequence Q8DRD2: RecName: Full=UPF0210 protein spr0218 {ECO:0000255|HAMAP-Rule:MF_01221};
- Comment: Glycine synthesis by Bifidobacterium breve or Methanococcus maripaludis requires two genes: a putative enzyme (distantly related to anaerobic ribonucleotide reductase), which we call glyXL, and an ACT domain protein, which we call glyXS (BBR_RS12920 and BBR_RS12915 or MMP_RS07345 and MMP_RS03450, Anthony Shiver and Leslie Day). These proteins are usually encoded next to each other (although not in Methanococcus). A homolog of glyXL from Streptococcus (spr0218, Q8DRD2) is also required for glycine synthesis (PMC2739083). Also, glyXS:glyXL is regulated by a glycine riboswitch in Bacillus methanolicus (see BMMGA3_03000 in PMC4342826).
- Total: 3 characterized proteins
glyXS: putative glycine synthesis enzyme, ACT domain component
- UniProt sequence Q8G509: RecName: Full=UPF0237 protein BL1209.1 {ECO:0000255|HAMAP-Rule:MF_01054};
- UniProt sequence Q6LZH1: RecName: Full=UPF0237 protein MMP0657 {ECO:0000255|HAMAP-Rule:MF_01054};
- Comment: Required for glycine synthesis along with glyXL in Bifodobacterium breve and Methanococcus maripaludis. ACT domain proteins often bind amino acids to regulate the activity of enzymes, so we predict that glyXL is the catalytic component.
- Total: 2 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