GapMind for catabolism of small carbon sources

 

Definition of L-lysine catabolism

As text, or see rules and steps

# Lysine degradation in GapMind is based on many metacyc pathways
# (metacyc:PWY-5327), including
# L-lysine degradation I via cadaverine (metacyc:PWY0-461),
# pathway IV via lysine monooxygenase (metacyc:PWY-5280),
# pathway V via D-lysine (metacyc:PWY-5283),
# pathway VI via lysine 6-aminotransferase (metacyc:PWY-5298),
# pathway VIII via lysine 6-dehydrogenase (metacyc:PWY-5314),
# and fermentation to acetate and butanoate (metacyc:P163-PWY).
# Pathway X (metacyc:PWY-6328) is similar to pathway I (with cadaverine and glutarate as intermediates), but
# glutarate is consumed via glutaryl-CoA (as in pathway IV);
# it does not introduce any new steps.
# Pathways II (L-pipecolate pathway)
# and III (via N6-acetyllysine)
# and VII (via 6-amino-2-oxohexanoate)
# and IX (similar to pathway IV)
# and XI (via saccharopine)
# are not thought to occur in prokaryotes and are not included in GapMind.

lysP	L-lysine:H+ symporter LysP	curated:CharProtDB::CH_003129	curated:CharProtDB::CH_091040	curated:CharProtDB::CH_091257	curated:CharProtDB::CH_091412	curated:SwissProt::A0A1D8PPG4	curated:SwissProt::A0A1D8PPI5	curated:SwissProt::A2RNZ6	curated:SwissProt::Q59WU0	curated:TCDB::K7VV21	curated:TCDB::P43059

# Transporters were identified using
# query: transporter:lysine:L-lysine:lys:L-lys
lysine-transport: lysP

LHT	L-lysine transporter	curated:SwissProt::Q9FKS8	curated:SwissProt::Q9LRB5	curated:SwissProt::Q9SX98	curated:TCDB::Q84WE9
lysine-transport: LHT

Slc7a1	L-lysine transporter Slc7a1	curated:CharProtDB::CH_091036	curated:CharProtDB::CH_091271	curated:CharProtDB::CH_091324
lysine-transport: Slc7a1

lysL	L-lysine transporter LysL	curated:CharProtDB::CH_019644
lysine-transport: lysL

# In E. coli and Salmonella, the ABC transporter has a lysine/arginine specific binding protein (argT),
# two permease subunits (hisQM, which are similar to each other), and an ATPase subunit (hisP).
# Pseudomonas aeruginosa has a homologous lysine transporter, PA5152-PA5155,
# as do various strains of Pseudomonas fluorescens.
# In P. putida, a similar system was identified using fitness data
#  (argT = PP_3593 = Q88GX4; hisQ = PP_3594 = Q88GX3; hisM = PP_3595 = Q88GX2; hisP = PP_3597 = Q88GX0).
# In S. meliloti, a similar substrate-binding protein was identified using fitness data (SMc00140 = Q92PA9),
#  but the ATPase subunit was not found (it might be shared with other systems).
argT	L-lysine ABC transporter, substrate-binding component ArgT	curated:CharProtDB::CH_003045	curated:TCDB::P09551	curated:TCDB::Q9HU31	curated:reanno::pseudo5_N2C3_1:AO356_05495	curated:reanno::pseudo5_N2C3_1:AO356_09900	curated:reanno::pseudo6_N2E2:Pf6N2E2_2958	uniprot:Q92PA9	uniprot:Q88GX4

hisM	L-lysine ABC transporter, permease component 1 (HisM)	curated:SwissProt::P0A2I7	curated:SwissProt::P0AEU3	curated:TCDB::Q9HU29	curated:reanno::pseudo5_N2C3_1:AO356_05505	curated:reanno::pseudo5_N2C3_1:AO356_09910	curated:reanno::pseudo6_N2E2:Pf6N2E2_2960	uniprot:Q88GX2

hisQ	L-lysine ABC transporter, permease component 2 (HisQ)	curated:SwissProt::P0A2I9	curated:SwissProt::P52094	curated:TCDB::Q9HU30	curated:reanno::pseudo5_N2C3_1:AO356_05500	curated:reanno::pseudo5_N2C3_1:AO356_09905	curated:reanno::pseudo6_N2E2:Pf6N2E2_2959	uniprot:Q88GX3

hisP	L-lysine ABC transporter, ATPase component HisP	curated:CharProtDB::CH_003210	curated:SwissProt::P02915	curated:TCDB::P73721	curated:TCDB::Q9HU32	curated:reanno::pseudo5_N2C3_1:AO356_05515	curated:reanno::pseudo5_N2C3_1:AO356_09895	curated:reanno::pseudo6_N2E2:Pf6N2E2_2962	uniprot:Q88GX0

lysine-transport: argT hisM hisQ hisP

# In Synechocystis, there is just one permease component fused to the
# substrate-binding component. The fusion protein is known as BgtB or BgtAB;
# BgtA is the hisP-like ATPase component.
bgtB	L-histidine ABC transporter, fused substrate-binding and permease components (BgtB/BgtAB)	curated:TCDB::P73544	curated:TCDB::Q8YSA2

lysine-transport: bgtB hisP

# Lysine exporters (LysE), porins, lysine:cadaverine antiporters
# (cadB), vacuolar transporters, lysosomal transporters, mitochondrial
# carrier proteins, and the schistosome amino acid transporter (TC
# 2.A.3.8.3) were excluded.

import leucine.steps:atoB # acetyl-CoA acetyltransferase is part of glutaryl-CoA degradation
import phenylacetate.steps:glutaryl-CoA-degradation

glaH	glutarate 2-hydroxylase, succinate-releasing (GlaH or CsiD)	EC:1.14.11.64

# As discussed in the MetaCyc page for lhgO (G1G01-3089-MONOMER),
# there is some controversy as to whether the E. coli enzyme (lhgD)
# uses quinone or oxygen as its acceptor; the Pseudomonas protein
# (G1G01-3089-MONOMER) does use oxygen.
lhgD	L-2-hydroxyglutarate dehydrogenase or oxidase (LhgD or LhgO)	EC:1.1.5.13	curated:metacyc::G1G01-3089-MONOMER	EC:1.1.99.2

# Glutarate is an intermediate in L-lysine degradation.  As part of
# MetaCyc pathway L-lysine degradation I (metacyc:PWY0-461), gluratate is hydroxylated
# to L-2-hydroxyglutarate (also known as (S)-2-hydroxyglutarate) by a
# 2-oxoglutarate-dependent oxidase. This reaction releases succinate
# (a TCA cycle intermediate) and CO2. A dehydrogenase then oxidizes to
# L-2-hydroxyglutarate to regenerate 2-oxoglutarate.
glutarate-degradation: glaH lhgD

gcdG	succinyl-CoA:glutarate CoA-transferase	EC:2.8.3.13

# Alternatively, as part of pathway IV (metacyc:PWY-5280),
# glutarate can be activated to glutaryl-CoA by a
# CoA-transferase. Glutaryl-CoA degradation (metacyc:PWY-5177)
# involves glutaryl-CoA dehydrogenase
# (decarboxylating) to crotonyl-CoA (trans-but-2-enoyl-CoA), hydration
# to (S)-hydroxybutanoyl-CoA, oxidization to acetoacetyl-CoA, and cleavage
# by a C-acetyltransferase to two acetyl-CoA.
glutarate-degradation: gcdG glutaryl-CoA-degradation

# Ignore some very-similar 4-aminobutyrate transaminases
davT	5-aminovalerate aminotransferase	EC:2.6.1.48	ignore:metacyc::MONOMER-11537	ignore:BRENDA::Q0K2K2
# Ignore some very-similar succinate-semialdehyde dehydrogenases
davD	glutarate semialdehyde dehydrogenase	EC:1.2.1.20	ignore:reanno::pseudo3_N2E3:AO353_11505	ignore:metacyc::MONOMER-15736	curated:SwissProt::Q9I6M5	ignore:BRENDA::P25526	ignore:metacyc::MONOMER-20455	ignore:reanno::MR1:200453

# 5-aminovalerate is an intermediate in L-lysine degradation (metacyc:PWY0-461, metacyc:PWY-5280).
# It is transaminated to glutarate semialdehyde and oxidized to glutarate.
# (A fermentative pathway via 5-hydroxyvalerate has also been reported, but
#  does not seem to be fully linked to sequence; see pathway 5 of PMID:11759672.)
5-aminovalerate-degradation: davT davD glutarate-degradation

# Q06191 is very similar to SMc04386 (P58350), which is specifically important for lysine
# utilization.
lysN	2-aminoadipate transaminase	EC:2.6.1.39	ignore:SwissProt::Q06191

# PP_5260 was shown to be form D-2-hydroxyglutarate (URL:https://doi.org/10.1101/450254).
# Homologous proteins that are specifically important for L-lysine utilization are
# also included. The E. coli homolog (ydcJ, G6738-MONOMER) also has this activity,
# see PMC7286885.
hglS	D-2-hydroxyglutarate synthase	curated:reanno::Putida:PP_5260	curated:reanno::pseudo5_N2C3_1:AO356_01105	curated:reanno::Smeli:SMc04383	curated:ecocyc::G6738-MONOMER

# PP_4493 was misannotated as EC 1.1.3.15, which acts on (S)-2-hydroxyglutarate.
# The E. coli homolog (ydiJ, ecocyc:G6913-MONOMER) does not seem to be characterized.
# SMc04384 (Q92L08) was identified using fitness data.
ydiJ	(R)-2-hydroxyglutarate dehydrogenase	EC:1.1.99.39	EC:1.1.99.40	curated:reanno::Putida:PP_4493	uniprot:Q92L08

# L-2-aminoadipate is an intermediate in L-lysine degradation
# pathways V and VI (metacyc:PWY-5283, metacyc:PWY-5298).
# A transaminase forms 2-oxoadipate, a oxygenase/decarboxylase
# (D-2-hydroxyglutarate synthase) forms (R)-2-hydroxyglutarate, and a
# dehydrogenase forms 2-oxoglutarate, which is an intermediate in the
# TCA cycle.
L-2-aminoadipate-degradation: lysN hglS ydiJ

# A0A0H3H393 is very similar to E. coli diaminopimelate decarboxylase
# and could not access the paper about it, so do not trust it.
cadA	lysine decarboxylase	EC:4.1.1.18	ignore:BRENDA::A0A0H3H393

# E. coli's putrescine aminotransferase (patA) is known to carry out
# this reaction as well.  I could not identify any evidence of other
# proteins that carry out this reaction (although it seems likely that
# other putrescine aminotransferases could).
patA	cadaverine aminotransferase	curated:metacyc::G7596-MONOMER

# E. coli 4-aminobutanal dehydrogenase (patD, P77674) is known to
# carry out this reaction.  It seems likely that other members of
# EC:1.2.1.19 (4-aminobutanal dehydrogenase) would perform it as well.
patD	5-aminopentanal dehydrogenase	curated:SwissProt::P77674	ignore_other:1.2.1.19

# In pathway I, lysine is decarboxylated by cadA to cadaverine (1,5-diaminopentane), transaminated
# to 5-aminopentanal by patA, and oxidized to 5-aminovalerate by patD.
all: lysine-transport cadA patA patD 5-aminovalerate-degradation

davB	L-lysine 2-monooxygenase	EC:1.13.12.2
davA	5-aminovaleramidase	EC:3.5.1.30

# In pathway IV, the monooxygenase/decarboxylase davB forms
# 5-aminopentanamide, which is hydrolyzed to 5-aminovalerate
# (5-aminopentanoate).
all: lysine-transport davB davA 5-aminovalerate-degradation

# Some lysine racemases are very similar to broad-specificity amino
# acid racemases (EC 5.1.1.10)
alr	lysine racemase	EC:5.1.1.5	ignore_other:5.1.1.10

# The ribosomal protein P80340 is misannotated in BRENDA
amaD	D-lysine oxidase	EC:1.4.3.3	ignore:BRENDA::P80340

dpkA	1-piperideine-2-carboxylate reductase	EC:1.5.1.1	EC:1.5.1.21

amaA	L-pipecolate oxidase	EC:1.5.3.7

# Q4L235 is misannotated in BRENDA.
# TIGR03443 hits both amaB and the ATP-hydrolyzing L-2-aminoadipate reductase.
# P83402 and P84463 are short sequence fragments.
# In MetaCyc, MONOMER-20455 is annotated as performing this reaction but was not given this EC number.
# PP_5258 (Q88CC3) is in a newer version of metacyc.
# SMc04385 (Q92L07) was identified using fitness data.
amaB	L-2-aminoadipate semialdehyde dehydrogenase (AmaB/Pcd)	EC:1.2.1.31	ignore:BRENDA::Q4L235	ignore_hmm:TIGR03443	ignore:SwissProt::P83402	ignore:SwissProt::P84463	curated:metacyc::MONOMER-12387	uniprot:Q88CC3	uniprot:Q92L07

# In pathway V, the racemase alr forms D-lysine, which is oxidized to 6-amino-2-oxo-hexanoate,
# spontaneously decarboxylates to 1-piperideine-2-carboxylate,
# a reductase forms L-pipecolate, an oxidase forms 1-piperideine-6-carboxylate,
# and a dehydrogenase forms L-2-aminoadipate.
all: lysine-transport alr amaD dpkA amaA amaB L-2-aminoadipate-degradation

lat	L-lysine 6-aminotransferase	EC:2.6.1.36

# In pathway VI, lysine 6-aminotransferase (lat) forms (S)-2-amino-6-oxohexanoate,
# which spontaenously dehydrates to 1-piperideine 6-carboxylate,
# and a dehydrogenase forms L-2-aminoadipate
all: lysine-transport lat amaB L-2-aminoadipate-degradation

lysDH	L-lysine 6-dehydrogenase	EC:1.4.1.18

# In pathway VIII, L-lysine 6-dehydrogenase (lysDH)
# forms (S)-2-amino-6-oxohexanoate, which spontaenously dehydrates to
# 1-piperideine 6-carboxylate, and a dehydrogenase forms
# L-2-aminoadipate.
all: lysine-transport lysDH amaB L-2-aminoadipate-degradation

kamA	L-lysine 2,3-aminomutase	EC:5.4.3.2
kamD	L-beta-lysine 5,6-aminomutase, alpha subunit	curated:BRENDA::Q8RHX7	curated:SwissProt::E3PRJ5
kamE	L-beta-lysine 5,6-aminomutase, beta subunit	curated:BRENDA::Q8RHX8	curated:SwissProt::E3PRJ4
kdd	3,5-diaminohexanoate dehydrogenase	EC:1.4.1.11
kce	(S)-5-amino-3-oxohexanoate cleavage enzyme	EC:2.3.1.247
kal	3-aminobutyryl-CoA deaminase	EC:4.3.1.14

# D9TQ00 is probably misannotated in BRENDA
# P52042 and metacyc::MONOMER-13470 and metacyc::MONOMER-11937 were given EC 1.3.8.1
# (which means electron transfer to etf, but no electron bifurcation expected),
# but are probably electron bifurcating
bcd	butanoyl-CoA dehydrogenase (NAD+, ferredoxin), dehydrogenase subunit	curated:BRENDA::D2RL84	curated:BRENDA::Q18AQ1	ignore:BRENDA::D9TQ00	curated:SwissProt::P52042	curated:metacyc::MONOMER-11937	curated:metacyc::MONOMER-13470

etfA	butanoyl-CoA dehydrogenase (NAD+, ferredoxin),  etfA subunit	curated:BRENDA::D2RIQ3	curated:BRENDA::Q18AQ5

etfB	butanoyl-CoA dehydrogenase (NAD+, ferredoxin),  etfB subunit	curated:BRENDA::D2RIQ2	curated:BRENDA::Q18AQ6

# cftAB are described in MetaCyc but are absent from the list of curated proteins
# in this version of GapMind
ctfA	butanoyl-CoA:acetoacetate CoA-transferase, alpha subunit	uniprot:P33752
ctfB	butanoyl-CoA:acetoacetate CoA-transferase, beta subunit	uniprot:P23673

# In the fermentative pathway, lysine 2,3-aminomutase (kamA) forms
# L-beta-lysine, another aminomutase forms
# (3S,5S)-3,5-diaminohexanoate, a dehydrogenase (deaminating) forms
# (S)-5-amino-3-oxohexanoate, a cleavage enzyme (thiolase) uses
# acetyl-CoA to form (S)-3-aminobutanoyl-CoA and acetoacetate, a
# deaminase forms crotonyl-CoA, a dehydrogenase forms butanoyl-CoA, a
# CoA-transferase converts the butanoyl-CoA and acetoacetate to
# butanoate (a waste product) and acetoacetyl-CoA, and a
# C-acetyltransferase (atoB) splits acetyl-CoA to two acetyl-CoA.
all: lysine-transport kamA kamD kamE kdd kce kal bcd etfA etfB ctfA ctfB atoB

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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:

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:

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:

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 preprint on GapMind for carbon sources, or view the source code.

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