Definition of L-arginine biosynthesis

As text, or see rules and steps

# Arginine biosynthesis in GapMind is based on MetaCyc pathways
# L-arginine biosynthesis I via L-acetyl-ornithine (metacyc:ARGSYN-PWY),
# II (acetyl cycle) (metacyc:ARGSYNBSUB-PWY),
# III via N-acetyl-L-citrulline (metacyc:PWY-5154),
# or IV via LysW-ornithine (metacyc:PWY-7400).
# GapMind also includes L-arginine biosynthesis with succinylated intermediates, as in Bacteroidetes (PMC5764234).
# These pathways all involve the activation of glutamate (by aceylation, succinylation, or attachment of LysW),
# followed by phosphorylation, reduction and transamination, to activated ornithine.
# In most pathways, this intermediate is cleaved to ornithine before transcarbamoylation,
# but in the N-acetylcitrulline or succinylated pathways, transcarbamoylation occurs before hydrolysis.
# In the final two steps, citrulline is converted to arginine by ArgG and ArgH.

# Bacteroidetes have a divergent N-acylglutamate synthase, see BT3761 (uniprot:Q8A1A5_BACTN)
# or Echvi_3845 (uniprot:L0G3H4_ECHVK).
# Bacteroides use succinylated intermediates (PMID:16704984), so their proteins are probably
# N-succinylglutamate synthases.
# (These enzymes are also known as argA2, see PMC9026213.)
# uniprot:Q8P8J6 is annotated as argB in BRENDA, but it is also argA (a fusion protein).
# N515DRAFT_3768 (uniprot:A0A1I2DIM7) is similar to ArgAB fusion proteins and mutants are rescued by arginine.
# It is not clear if mnaT (ecocyc:G6759-MONOMER) would acetylate arginine, so it is ignored.
# Some EC 2.3.1.35 enzymes are probably dedicated for converting N-acetylornithine back to ornithine,
# while others are bifunctional for N-acetylglutamate formation as well (argJ);
# so similarity to this EC number is inconclusive.
# For some CharProtDB entries it is unclear if they have this activity or not, while others are
# labeled with this function but without the EC number.
# uniprot:Q9I3W7 is annotated as this in BRENDA but we did not find experimental evidence of its activity
# on glutamate, so it is ignored.
# In Steroidobacter denitrificans, argA is missing but the arginine synthesis cluster includes a
# potential N-acetyltransferase ACG33_RS14135 (uniprot:A0A127FCT3). Homologs of this protein are
# conserved in the cluster, and it is never found together with argA; it is distantly related to
# D-glutamate acetyltransferase dgcN (formerly DUF1611, see PMC10030869).
argA	N-acylglutamate synthase	EC:2.3.1.1	term:N-succinylglutamate synthase	uniprot:Q8A1A5_BACTN	uniprot:L0G3H4_ECHVK	curated:BRENDA::A0A0H2X8L7	curated:BRENDA::Q8P8J6	ignore:ecocyc::G6759-MONOMER	ignore_other:EC 2.3.1.35	ignore:CharProtDB::CH_123299	curated:CharProtDB::CH_122594	ignore:BRENDA::Q9I3W7	ignore:BRENDA::Q8P8J6	predicted:A0A127FCT3

# ArgB includes Bacteroides proteins that act on N-succinylglutamate instead
# of the usual N-acetylglutamate (i.e. BT3395).
# See "Discovery of novel pathways of microbial arginine biosynthesis" (2010),
# PhD thesis of Juan Manuel Cabrera Luque, which shows that argB from B. fragilis is
# N-succinylglutamate kinase.
# uniprot:O67848 in BRENDA seems likely to be argB but is misannotated as a deacetylase;
# also, uniprot:Q87EL2 is likely to be argB as well as argA.
# CH_123299 has a broader annotation but probably has this activity.
#
argB	N-acylglutamate kinase	EC:2.7.2.8	term:N-succinylglutamate kinase	ignore:BRENDA::O67848	ignore:BRENDA::Q87EL2	curated:CharProtDB::CH_123299

# ArgC includes Bacteroides proteins that probably act
# on N-succinylglutamylphosphate instead of N-acetylglutamylphosphate (i.e. BT3759).
# CH_123299 has a broader annotation but probably has this activity.
# HP15_352 (uniprot:E4PLW0) from Marinobacter adhaerens HP15 is important for fitness in most
# minimal media, unless arginine is provided.
argC	N-acylglutamylphosphate reductase	EC:1.2.1.38	term:N-succinylglutamylphosphate reductase	curated:CharProtDB::CH_123299	uniprot:E4PLW0

# This aminotransferase for converting N-acetylglutamate semialdehyde to acetylornithine is
# often similar to succinylornithine transaminases (EC:2.6.1.81),
# 4-aminobutyrate aminotransferases (EC:2.6.1.19), or 
# 5-aminovalerate transaminases (EC:2.6.1.48). (Succinylornithine and 4-aminobutyrate transaminases
# are also reported to be active on N-acetylornithine and this seems likely for 5-aminovalerate
# transaminases as well.)
# metacyc:MONOMER-18314 is given this EC nmber but is actually LysW-lysine/ornithine aminotransferase (LysJ).
# PMID:A0A806JQF3 show that Rv1655 (uniprot:A0A806JQF3) from Mycobacterium tuberculosis is argD.
argD	N-acetylornithine aminotransferase	EC:2.6.1.11	ignore_other:EC 2.6.1.81	ignore_other:EC 2.6.1.19	ignore:metacyc::MONOMER-18314	ignore_other:EC 2.6.1.48	uniprot:A0A806JQF3

# This EC number also includes N-acetylcitrulline deacetylase, which is part of pathway III.
# A putative amidohydrolase "ArgA3" (W3Y6L2) is in a conserved
# operon with ornithine carbamoyltransferase (the next step) in Veillonella and
# related genera (PMC9026213). The genome context includes other
# arginine synthesis genes as well. Although ArgA3 was proposed to be a N-acetylglutamate
# synthase, it is related to N-acetyl-cysteine deacetylase, and the genomes with "ArgA3"
# are lacking argE as well; so we think argE is the more likely function.
argE	N-acetylornithine deacetylase	EC:3.5.1.16	term:N-acetylcitrulline deacetylase	predicted:W3Y6L2

# This could obtain the amino group from glutamine (EC:6.3.5.5) or from ammonia (EC:6.3.4.16)
carA	carbamoyl phosphate synthase subunit alpha	term:carbamoyl-phosphate synthase%small	ignore_other:EC 6.3.5.5	ignore_other:EC 6.3.4.16	hmm:TIGR01368
carB	carbamoyl phosphate synthase subunit beta	term:carbamoyl-phosphate synthetase%large	term:carbamoyl-phosphate synthase%large	ignore_other:EC 6.3.5.5	ignore_other:EC 6.3.4.16	hmm:TIGR01369

# ArgI converts ornithine to citrulline. (E. coli has two paralogs, argI and argF.)
# Some putrescine carbamoyltransferases (EC 2.1.3.6) are also active on ornithine (uniprot:Q837U7) so
# any similarity to those is ignored.
argI	ornithine carbamoyltransferase	EC:2.1.3.3	ignore_other:EC 2.1.3.6

# ArgG converts citrulline + aspartate to arginosuccinate.
# N515DRAFT_3766 (uniprot:A0A1I2DIG3_9GAMM) and BT3768 (uniprot:Q8A1A6_BACTN) are diverged
# and mutants are auxotrophic & rescued by arginine
argG	arginosuccinate synthetase	EC:6.3.4.5	uniprot:A0A1I2DIG3_9GAMM	uniprot:Q8A1A6_BACTN

# Some ArgH proteins also funciton as Delta crystallin I, so ignore any similarity to those (even
# proteins not so annotated may be bifuncational).
argH	argininosuccinate lyase	EC:4.3.2.1	term:argininosuccinate lyase	term:arginosuccinate lyase	ignore_other:Delta crystallin

### Bacteroidetes pathway with succinylated intermediates
# This pathway is inferrred from a N-succinylornithine
# carbamoyltransferase (argF'B; EC 2.1.3.11) -- see
# https://www.ncbi.nlm.nih.gov/pubmed/16704984
# As discussed above the N-acylglutamate synthase (ArgA) is diverged
# and apparently acts forms N-succinylglutamate instead.  The next
# steps (ArgB and ArgC) might not be specific for N-acetyl
# vs. N-succinyl substrates, or the Bacteroidetes genes may have
# adapted to prefer N-succinyl intermediates.  The conversion of
# N-succinylgutamate semialdehyde to N-succinylornithine is probably
# carried out by a diverged argD (argD'B below), which would produce
# the substrate for argF'B.  And a diverged desuccinylase (argE'B
# below) probably acts on N-succinylornithine, because these
# Bacteroidetes have ordinary argG/argH for the conversion of
# ornithine to arginine

# N-succinylglutamate semialdehyde => N-succinylornithine.
# Some Bacteroides hvae a diverged argD-like gene, i.e. BT3758 (uniprot:Q8A1A8) or Echvi_3848 (uniprot:L0G5F2_ECHVK),
# which are auxotrophic and cofit with other arg genes.
# Note that this is the same reaction as found in arginine degradation by the arginine succinyltransferase (AST) pathway
argD'B	N-succinylornithine aminotransferase	EC:2.6.1.81	uniprot:Q8A1A8	uniprot:L0G5F2_ECHVK	ignore_other:EC 2.6.1.11

# In, Bacteroides fragilis, argF'B converts N-succinylornithine to N-succinylcitrulline
# (PMID:16704984). Echvi_3849 (uniprot:L0G4Z0_ECHVK) also has this activity, as it is rescued by arginine
# and Echinicola vietnamensis has similar argD'/argE'
argF'B	N-succinylornithine carbamoyltransferase	EC:2.1.3.11	uniprot:L0G4Z0_ECHVK

# The N-succinylcitrulline desuccinylase is probably BT3549 (uniprot:Q8A1V9),
# Echvi_3851 (uniprot:L0G443_ECHVK), or CA265_RS18500 (uniprot:A0A1X9Z8E1_9SPHI)
# Mutants in these genes are rescued by added arginine and they are
# distantly related to succinyl-diaminopimelate desuccinylase.
# And these bacteria have ordinary argG/argH, so citrulline is expected to be an intermediate.
argE'B	N-succinylcitrulline desuccinylase	term:N-succinylcitrulline desuccinylase

# In pathway II (acetyl cycle), instead of an acetylornithine deacetylase,
# the acetyltransferase argJ converts N-acetylornithine to ornithine.
# ArgJ may also form N-acetylglutamate (replacing argA).
# CH_122594 lacks an EC number (not fully characterized) and is likely to be ArgJ (50% identity to uniprot:O94346)
argJ	ornithine acetyltransferase	EC:2.3.1.35	ignore:CharProtDB::CH_122594

# MetaCyc pathway L-arginine biosynthesis III via N-acetyl-L-citrulline

# Instead of deacetylating N-acetyl-ornithine, it is carbamoylated to N-succinylcitrulline and then deacetylated.
# (This deacetylation reaction has the same EC number as acetylornithine deacetylase,
# so both are included in argE.)
argF'	acetylornithine transcarbamoylase	EC:2.1.3.9

# LysW is amino group carrier protein
import lys.steps:lysW

# There is also an archaeal pathway from glutamate to ornithine with LysW as the carrier protein, instead
# of N-acyl intermediates. This pathway is analogous to the conversion of alpha-aminoadipate to
# lysine, and many of the enzymes are bifunctional. But the initial ligation of LysW to arginine
# has a dedicated enzyme in many archaea.
# uniprot:Q970U6 is given a generic EC number in SwissProt, but has this function.
# EC:6.4.2.43 (LysW-2-aminoadipate ligases) are ignored because some are bifunctional (PMC5076833).
argX	glutamate--LysW ligase	EC:6.3.2.60	curated:SwissProt::Q970U6	ignore_other:6.3.2.43

# TK0276 from Thermococcus kodakarensis (uniprot:Q5JFW2) is bifunctional, for lysine and ornithine synthesis (PMC5076833).
# In Haloferax volcanii, the putative [LysW]-glutamate kinase (HVO_RS04915, uniprot:D4GYN9) is in a
# conserved operon with LysW and with other arginine synthesis genes; this protein is more similar to
# a characterized [LysW]-2-aminoadipate 6-kinase, but haloarchaea do not use the aminoadipate pathway
# (PMC93780, PMC8305020).
lysZ	[LysW]-glutamate kinase	EC:2.7.2.19	uniprot:Q5JFW2	predicted:D4GYN9

# TK0277 from Thermococcus kodakarensis (uniprot:Q5JFW1) is bifunctional, for lysine and ornithine synthesis (PMC5076833).
lysY	[LysW]-glutamate-6-phosphate reductase	EC:1.2.1.106	uniprot:Q5JFW1

# TK0275 from Thermococcus kodakarensis (uniprot:Q5JFW3) is bifunctional, for lysine and ornithine synthesis (PMC5076833).
# Similarity to EC:2.6.1.118 ([LysW]-aminoadipate semialdehyde aminotransferase) is ignored because some are bifunctional (PMC5076833).
lysJ	[LysW]-glutamate-semialdehyde aminotransferase	EC:2.6.1.124	ignore_other:2.6.1.118

# TK0274 from Thermococcus kodakarensis (uniprot:Q5JFW4) is bifunctional, for lysine and ornithine synthesis (PMC5076833).
lysK	[LysW]-ornithine hydrolase	EC:3.5.1.132

# In L-arginine biosynthesis I, ornithine forms via acetylated intermediates, argA, and argE (metacyc:ARGSYN-PWY).
ornithine: argA argB argC argD argE

# In L-arginine biosynthesis II, ornithine forms via acetylated intermediates and argJ (metacyc:ARGSYNBSUB-PWY).
ornithine: argJ argB argC argD

# In L-arginine biosynthesis IV, ornithine forms via LysW-modified intermediates (metacyc:PWY-7400).
ornithine: lysW argX lysZ lysY lysJ lysK 

# In pathways I, II, or IV, ornithine is carbamoylated by argI.
all: ornithine carA carB argI argG argH

# In pathway III (N-acetylcitrulline), N-acetylornithine is carbamoylated by argF'
# and N-acetylcitrulline is hydrolyzed by argE.
all: argA argB argC argD carA carB argF' argE argG argH

# In the pathway with succinylated intermediates, N-succinylornithine is carbamoylated by argF'B.
all: argA argB argC argD'B argF'B argE'B argG argH