Definition of L-serine biosynthesis

GapMind for Amino acid biosynthesis

Definition of L-serine biosynthesis

# Serine biosynthesis in GapMind is based on MetaCyc pathway
# L-serine biosynthesis I (metacyc:SERSYN-PWY).
# Pathway II (metacyc:PWY-8011) 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.)

# 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 (uniprot: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 (uniprot:Q6LWW6) was identified as the serA of Methanococcus (PMC1797378).
# Ignore metacyc:HP_RS05420-MONOMER which has this EC but has a different function.
# Ignore similarity to sll1908 (metacyc:SGL_RS08600-MONOMER) which seems likely to be serA but
# was proposed (without experimental evidence) to be hydroxpyruvate reductase.
# In Roseburia faecis, the putative serA (uniprot:A0A374I5P9) is diverged but is similar to the serA part of Echvi_2777
# and is conserved next to serC and DUF1015 (putative serB).
serA	3-phosphoglycerate dehydrogenase	EC:1.1.1.95	uniprot:A0A1X9ZCD3	uniprot:Q6LWW6	ignore:BRENDA::Q4JDI4	ignore:metacyc::HP_RS05420-MONOMER	ignore:metacyc::SGL_RS08600-MONOMER	predicted:A0A374I5P9

# MJ0959 (uniprot: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)
serC	3-phosphoserine aminotransferase	EC:2.6.1.52	uniprot:Y959_METJA	uniprot:Q2FXK2	predicted:A5I0W7	predicted:A0A843E9R6	predicted:A0A1T4W7T3

# 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 (uniprot:P60487, uniprot:Q96GD0, uniprot:Q3ZBF9, uniprot:P00634,
# uniprot:P0AE22, uniprot:Q9P376, uniprot:O07014).
# Similarly, Swiss-Prot annotates RsbX (uniprot:P17906) and RsbU (uniprot:P40399) with this EC number, but
# they probably act on proteins.
# And, AraL (uniprot:P94526) is ignored because although it does have activity on phosphoserine, it is a
# promiscuous phosphatase (supplementary material of PMC4413258).
# PMID:25848029 does show that BH2972 (uniprot:Q9K8N3) and X3MFA4 (now uniprot:A0A1R2PVY2) have this activity.
# 5zr2C (uniprot:N9V397) is serB in Entamoeba histolytica (see PMID:30935984)
# In Clostridiodes difficile, the serine synthesis operon includes CDIF630erm_01132, a DUF1015
# protein which is speculated to replace serB (PMC6110889). This subfamily is usually colocated
# with serA or serC3 (see ADT23_RS05570 or uniprot: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.
serB	phosphoserine phosphatase	EC:3.1.3.3	ignore_other:EC 1.1.1.95	ignore:SwissProt::P60487	ignore:SwissProt::Q96GD0	ignore:SwissProt::Q9P376	ignore:BRENDA::O07014	ignore:SwissProt::Q3ZBF9	ignore:BRENDA::P00634	ignore:SwissProt::P0AE22	ignore:SwissProt::P17906	ignore:SwissProt::P40399	ignore:SwissProt::P94526	uniprot:Q9K8N3	uniprot:A0A1R2PVY2	uniprot:N9V397	predicted:A0A6B4WGC7

all: serA serC serB

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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
the source code
instructions for running GapMind on your computer
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

GapMind for Amino acid biosynthesis