Definition of L-lysine biosynthesis

GapMind for Amino acid biosynthesis

Definition of L-lysine biosynthesis

# Lysine biosynthesis in GapMind is based on MetaCyc
# pathways L-lysine biosynthesis I via diaminopimelate (DAP) and
# succinylated intermediates (metacyc:DAPLYSINESYN-PWY),
# II with DAP and acetylated intermediates (metacyc:PWY-2941),
# III with DAP and no blocking group (metacyc:PWY-2942),
# V via 2-aminoadipate and LysW carrier protein (metacyc:PWY-3081),
# and VI with DAP aminotransferase (metacyc:PWY-5097).
# Most of these pathways involve tetrahydrodipicolinate
# and meso-diaminopimelate, with variations in how the amino group is introduced.
# Pathway V instead involves L-2-aminoadipate and LysW-attached intermediates.
# Lysine biosynthesis IV (metacyc:LYSINE-AMINOAD-PWY), via 2-aminoadipate and saccharopine,
# is only reported to occur in eukaryotes and is not described here.

import met.steps:aspartate-semialdehyde

# uniprot:Q3MFY8, uniprot:Q3M723, and many proteins form Agrobacterium tumefaciens are misannotated in BRENDA,
# and are ignored.
# (The reference for those points at gene 1133062 = Atu1024 as the synthase instead, and states that
# the other Agrobacterium dapA-like proteins lack this activity, see PMID:24677246.)
# uniprot:Q8A3Z0 is annotated as this in BRENDA, but the cited paper does not demonstrate this activity,
# and another protein (BT0895) appears to be the major dapA in Bacteroides thetaiotaomicron,
# (it is essentail), so Q8A3Z0 is ignored.
dapA	4-hydroxy-tetrahydrodipicolinate synthase	EC:4.3.3.7	EC:4.2.1.52	ignore:BRENDA::Q3MFY8	ignore:BRENDA::Q3M723	ignore:BRENDA::A9CGZ4	ignore:BRENDA::A9CHR2	ignore:BRENDA::A9CL94	ignore:BRENDA::A9CL97	ignore:BRENDA::Q7D0E8	ignore:BRENDA::Q7D313	ignore:BRENDA::Q8A3Z0

# Formerly known as dihydrodipicolinate reductase.
# Echvi_2395 (uniprot:L0G028_ECHVK) and CA265_RS15670 (uniprot:A0A1X9Z7Q6_9SPHI) are somewhat diverged,
# but conserved essentiality confirms they are dapB.
# uniprot:Q3MFY8 is misannotated in BRENDA, so it is added manually.
# uniprot:Q3M723 is misannotated in BRENDA, so it is ignored.
dapB	4-hydroxy-tetrahydrodipicolinate reductase	EC:1.17.1.8	uniprot:L0G028_ECHVK	uniprot:A0A1X9Z7Q6_9SPHI	curated:BRENDA::Q3MFY8	ignore:BRENDA::Q3M723

# Formerly known as 2,3,4,5-tetrahydropyridine-2-carboxylate N-succinyltransferase
dapD	tetrahydrodipicolinate succinylase	EC:2.3.1.117

# 2.6.1.52 is the EC number for 3-phosphoserine aminotransferase (serC), which catalyzes
# this reaction in E. coli.
# The function of uniprot:O50434 is not known, so similarity to it is ignored.
# E.coli's succinylornithine transaminase has this activity as well (PMID:25243376), so
# similarity to succinylornithine transaminases (EC:2.6.1.81) is ignored.
dapC	N-succinyldiaminopimelate aminotransferase	EC:2.6.1.17	EC:2.6.1.52	ignore:SwissProt::O50434	ignore_other:EC 2.6.1.81

dapE	succinyl-diaminopimelate desuccinylase	EC:3.5.1.18

# L,L-diaminopimelate to meso-diaminopimelate.
# A putative amino acid racemase (A0A9Q5JK70) is in a conserved operon with lysA ("dapF2" in PMC9026213);
# it is likely to be a diaminopimelate epimerase.
dapF	diaminopimelate epimerase	EC:5.1.1.7	predicted:A0A9Q5JK70

# A0A0H3H393 is reported to be a lysine decarboxylase but is 87% identical to E. coli's
# diaminopimelate decarboxylase, so it is ignored.
# CALK_RS03395 (uniprot:U7D9L6) has conserved functional residues (see alignment to 1ko0A) and is in an operon with
# meso-diaminopimelate D-dehydrogenase (ddh), so it must be the missing lysA.
# MetaCyc annotates THAPSDRAFT_20613 (metacyc:MONOMER-21197), which is probably a diaminopimelate decarboxylase,
# as a dimethylsulfonio-2-hydroxybutanoate hydroxylase/decarboxylase, but there is no experimental evidence, so
# it is ignored.
lysA	diaminopimelate decarboxylase	EC:4.1.1.20	ignore:BRENDA::A0A0H3H393	predicted:U7D9L6	ignore:metacyc::MONOMER-21197

# Also known as ykuQ
dapH	tetrahydrodipicolinate acetyltransferase	EC:2.3.1.89

# Also known as patA in Bacillus subtilis
dapX	acetyl-diaminopimelate aminotransferase	term:N-acetyl-LL-diaminopimelate aminotransferase

# Also known as ykuR or DapeL. The putative amidohydrolase
# AA076_RS07060 (Q2FH40) from Staphylococcus is conserved near dapX
# and/or lysA and is similar to N-acetylcysteine deacetylase, so we
# predict that it is a N-acetyl-diaminopimelate deacetylase.
dapL	N-acetyl-diaminopimelate deacetylase	EC:3.5.1.47	predicted:Q2FH40

# In reverse, this converts tetrahydrodipicolinate to meso-DAP.
ddh	meso-diaminopimelate D-dehydrogenase	EC:1.4.1.16

# This enzyme is sometimes known as dapL. In reverse, it converts tetrahydrodipicolinate to L,L-DAP.
DAPtransferase	L,L-diaminopimelate aminotransferase	EC:2.6.1.83

# forming (2R)-homocitrate
hcs	homocitrate synthase	EC:2.3.3.14

# (2R)-homocitrate to (1R,2S)-homoisocitrate via cis-homoaconitate
lysT	homoaconitase large subunit	term:homoaconitase large subunit	ignore_other:EC 4.2.1.114	ignore_other:EC 4.2.1.36
lysU	homoaconitase small subunit	term:homoaconitase small subunit	ignore_other:EC 4.2.1.114	ignore_other:EC 4.2.1.36

# homoisocitrate to 2-oxoadipate. This rule also matches some isocitrate/homoisocitrate dehydrogenases (1.1.1.286)
# which often have multiple subunits in eukaryotes; this is not represented here.
hicdh	homo-isocitrate dehydrogenase	EC:1.1.1.87	EC:1.1.1.286

# 2-oxoadipate to 2-aminoadipate.
# uniprot:Q06191 is very simlar to SMc04386, which seems to have this activity 
# (it is required for lysine utilization), and as far as we know, Q06191 has not been tested
# for activity on 2-aminoadipate, so it is ignored
lysN	2-aminoadipate:2-oxoglutarate aminotransferase	EC:2.6.1.39	ignore:SwissProt::Q06191

# LysW is a carrier protein for intermediates in lysine and/or ornithine biosynthesis.
# It is sometimes called the amino group carrier protein.
# TK0279 (uniprot:Q5JFV9) from Thermococcus kodakarensis was characterized, see PMC5076833.
lysW	2-aminoadipate/glutamate carrier protein	term:alpha-aminoadipate%carrier	uniprot:Q5JFV9

# A5U2Z7 and BRENDA::P9WFU7 are misannotated in BRENDA.
# TK0278 from Thermococcus kodakarensis (uniprot:Q5JFW0) is bifunctional, for lysine and ornithine synthesis (PMC5076833).
lysX	2-aminoadipate-LysW ligase	EC:6.3.2.43	ignore:BRENDA::A5U2Z7	ignore:BRENDA::P9WFU7	uniprot:Q5JFW0

# TK0276 from Thermococcus kodakarensis (uniprot:Q5JFW2) is bifunctional, for lysine and ornithine synthesis (PMC5076833).
lysZ	[LysW]-2-aminoadipate 6-kinase	EC:2.7.2.17	uniprot:Q5JFW2

# TK0277 (uniprot:Q5JFW1) is bifunctional, for lysine and arginine synthesis (PMC5076833).
lysY	[LysW]-2-aminoadipate 6-phosphate reductase	EC:1.2.1.103	curated:BRENDA::Q5JFW1

# TK0275 from Thermococcus kodakarensis (uniprot:Q5JFW3) has also been characterized (PMC5076833).
lysJ	[LysW]-2-aminoadipate semialdehyde transaminase	EC:2.6.1.118	EC:2.6.1.124	uniprot:Q5JFW3

# TK0274 from Thermococcus kodakarensis (uniprot:Q5JFW4) is bifunctional, for lysine and ornithine synthesis (PMC5076833).
lysK	[LysW]-lysine hydrolase	EC:3.5.1.130	uniprot:Q5JFW4

# (S)-2,3,4,5-tetrahydrodipicolinate is formed from aspartate semialdehyde by dapAB.
# In pathway I (dapDCE), it is succinylated, transaminated, and desuccinyulated, to L,L-DAP,
# and then the epimerase dapF forms meso-DAP.
# Pathway II (dapHXL) is similar but with acetylated intermediates.
# In pathway III, tetrahydrodipicolinate is reductively aminated to meso-DAP in one step, by ddh.
# In pathway VI, an aminotransferase (DAPtransferase) forms L,L-DAP.
meso-DAP: aspartate-semialdehyde dapA dapB dapD dapC dapE dapF
meso-DAP: aspartate-semialdehyde dapA dapB dapH dapX dapL dapF
meso-DAP: aspartate-semialdehyde dapA dapB ddh
meso-DAP: aspartate-semialdehyde dapA dapB DAPtransferase dapF

# 2-oxoglutarate and acetyl-CoA are converted to homocysteine, homoaconitate and then 2-oxoadipate (by hcs-lysTU-hicdh),
# an aminotransferase (lysN) forms L-2-aminoadipate, lysX ligates 2-aminoadipate to lysW,
# lysZYJ convert LysW-aminoadipate to LysW-lysine, and lysK releases lysine.
lysW-pathway: hcs lysT lysU hicdh lysN lysW lysX lysZ lysY lysJ lysK

all: meso-DAP lysA
all: lysW-pathway

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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