Definition of L-histidine biosynthesis

GapMind for Amino acid biosynthesis

Definition of L-histidine biosynthesis

# Histidine biosynthesis in GapMind is based on the MetaCyc pathway (metacyc:HISTSYN-PWY).

prs	ribose-phosphate diphosphokinase	EC:2.7.6.1

hisG	ATP phosphoribosyltransferase	EC:2.4.2.17

# CH_123581 and uniprot:A1BPP9 probably do all three: hisD, hisE, and hisI.
hisI	phosphoribosyl-ATP pyrophosphatase	EC:3.6.1.31	ignore:CharProtDB::CH_123581	ignore:BRENDA::A1BPP9

# uniprot:A1BPP9 is annotated as hisD but is likely multifunctional, so similarity to it is ignored.
hisE	phosphoribosyl-AMP cyclohydrolase	EC:3.5.4.19	hmm:PF01502	ignore:CharProtDB::CH_123581	ignore:BRENDA::A1BPP9

hisA	1-(5-phosphoribosyl)-5-[(5-phosphoribosylamino)methylideneamino]imidazole-4-carboxamide isomerase	EC:5.3.1.16

# Subunits are not always annotated consistently, so are added manually, and uniprot:Q9SZ30 is a fusion protein of the two subunits
hisF	imidazole glycerol phosphate synthase, cyclase subunit	term:hisF	hmm:TIGR00735	ignore_other:imidazole glycerol phosphate synthase	curated:BRENDA::Q5NMD6	curated:BRENDA::Q8ZY16	curated:BRENDA::A4WHB6	curated:BRENDA::Q9SZ30

# Subunits are not always annotated consistently, so are added manually, and uniprot:Q9SZ30 is a fusion protein of the two subunits
hisH	imidazole glycerol phosphate synthase, amidotransferase subunit	term:hisH	term:IGP synthase, amidotransferase subunit	hmm:TIGR01855	ignore_other:imidazole glycerol phosphate synthase	curated:BRENDA::Q5NMD4	curated:BRENDA::Q8ZY40	curated:BRENDA::Q9SZ30	curated:BRENDA::A4WHA5

# Fitness data showed that BPHYT_RS17700 (B2SZ63) from Burkholderia phytofirmans is required for histidine biosynthesis.
# PA5143 (Q9HU41) from Pseudomonas aeruginosa is required for histidine biosynthesis (PMC7028973).
hisB	imidazoleglycerol-phosphate dehydratase	EC:4.2.1.19	uniprot:B2SZ63	uniprot:Q9HU41

# In Bacillus subtilis, the histidinol-phosphate aminotransferase activity is provided by a gene that is in a cluster of
# genes for tyrosine and phenylalanine biosynthesis (PMID:4431). Homology suggests that this
# activity is provided by "HisH" (BSU22620), which indeed is just upstream of tyrA (PMID:6092865).
# This protein is now usually referred to as "HisC" (uniprot:HIS8_BACSU).
# GAMENC_05715 from Acidovorax sp. FHTAMBA (nearly identical to uniprot:A0A2R7PAQ8) can complement a hisC- strain of E. coli (Bradley Biggs) and is in a histidine synthesis gene cluster.
# GW822FHT02A01_217 from Rhodoferax sp. GW822-FHT02A01 (similar to uniprot:A0A975E8Y9) can complement a hisC- strain of E. coli (Bradley Biggs) and is in a histidine synthesis gene cluster.
# Fitness data for BPHYT_RS14905 from Burkholderia phytofirmans suggests that it is an aromatic amino acid transaminase,
# but it is 55% identical to TK06_RS12685, which can complement a hisC- mutant of E.coli (Bradley Biggs),
# so any similarity to it is ignored.
hisC	histidinol-phosphate aminotransferase	EC:2.6.1.9	uniprot:HIS8_BACSU	uniprot:A0A2R7PAQ8	uniprot:A0A975E8Y9	ignore:reanno::BFirm:BPHYT_RS14905

# In Bacillus subtilis and some related bacteria, histidinol-phosphate phosphatase is known as HisJ
# and has been confirmed by biochemical assays of purified proteins (PMC3570733).
# The identifiers given (see their Table 3) are
# MCCL_0344 BBR47_00270 BCE_1533 BcerKBAB4_1335 BcerKBAB4_1335 BSU29620 BH3206 GK2799 SMU_1486c
# (uniprot:B9E9Z0_MACCJ uniprot:C0ZH63_BREBN uniprot:Q73B87_BACC1 uniprot:A9VLI0_BACMK uniprot:HIS9_BACHD
# uniprot:Q5KW52_GEOKA uniprot:Q8DT80_STRMU uniprot:HIS9_BACSU).
# In Bifidobacterium breve, the phosphatase activity is provided by Bbr_0982 (uniprot:A0A0L7BRC5,
# URL:https://doi.org/10.1101/2023.08.29.555234).
# uniprot:S5FT07 and uniprot:S5FU55 are misannotated as this in BRENDA.
# E. coli phoA (ecocyc:ALKAPHOSPHA-MONOMER) has this activity but is ignored because it is periplasmic.
hisN	histidinol-phosphate phosphatase	EC:3.1.3.15	uniprot:B9E9Z0_MACCJ	uniprot:C0ZH63_BREBN	uniprot:Q73B87_BACC1	uniprot:A9VLI0_BACMK	uniprot:HIS9_BACHD	uniprot:Q5KW52_GEOKA	uniprot:Q8DT80_STRMU	uniprot:HIS9_BACSU	uniprot:A0A0L7BRC5	ignore:BRENDA::S5FT07	ignore:BRENDA::S5FU55	ignore:ecocyc::ALKAPHOSPHA-MONOMER

hisD	histidinal/histidinol dehydrogenase	EC:1.1.1.23	ignore:CharProtDB::CH_123581

all: prs hisG hisI hisE hisA hisF hisH hisB hisC hisN hisD

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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