Definition of L-lactate catabolism

GapMind for catabolism of small carbon sources

Definition of L-lactate catabolism

# L-lactate degradation in GapMind is based on L-lactate dehydrogenases or oxidases.

# E. coli GlcA (Q46839) is similar to LctP and is reported to transport both L- and D-lactate.
# PS417_24105 (GFF4172) is important only for D-lactate utilization but is closely related to AO356_07550
# and could be an L-lactate transporter as well.
# SO_1522 (Q8EGS2) and Psest_0955 (L0GFN1) probably transport both isomers.
# Bacillus subtilis LutP (uniprot:P71067) is an L-lactate transporter.
lctP	L-lactate:H+ symporter LctP or LidP	curated:SwissProt::P33231	curated:SwissProt::P71067	curated:reanno::pseudo5_N2C3_1:AO356_07550	curated:TCDB::Q46839	ignore:reanno::WCS417:GFF4712	uniprot:Q8EGS2	uniprot:L0GFN1	curated:SwissProt::P71067

# Transporters were identified using
# query: transporter:L-lactate:(S)-lactate:D,L-lactic
# and prokaryotic lactate transporters were examined as well.
# Exchangers for lactate/citrate or lactate/malate were ignored.
L-lactate-transport: lctP

SfMCT	L-lactate transporter SfMCT	curated:SwissProt::A0LNN5
L-lactate-transport: SfMCT

larD	D,L-lactic acid transporter LarD	curated:SwissProt::F9UST3	curated:SwissProt::F9UMX3
L-lactate-transport: larD

mctP	D,L-lactic acid transporter MctP	curated:TCDB::Q8VM88	curated:SwissProt::Q1M7A2
L-lactate-transport: mctP

# 2-component L-lactate transporter from Shewanella loihica PV-4.  A
# related system in Shewanella amazonesnsis SB2B is also probably a
# L-lactate transporter (SB2B cannot utilize D-lactate), but its
# specificity is not proven, so it is marked ignore.
Shew_2731	L-lactate:Na+ symporter, large component	curated:reanno::PV4:5209923	ignore:reanno::SB2B:6937353
Shew_2732	L-lactate:Na+ symporter, small component	curated:reanno::PV4:5209924	ignore:reanno::SB2B:6937352
L-lactate-transport: Shew_2731 Shew_2732

# TLBP_THET8 / Q5SK82 is thought to be the periplasmic
# substrate-binding component of a TRAP system, and has been shown to
# bind calcium L-lactate (the calcium can be replaced by other
# divalent ions; PMID:19631222). However the other components of this
# putative TRAP system have not been studied.

# F8SVK1 (TC 2.A.1.6.11) seems to be a weak lactate transporter, so ignore

# A0A0H3W5K4/I3VSF1 appears to be misannotated in BRENDA
L-LDH	L-lactate dehydrogenase	EC:1.1.2.3	EC:1.1.1.27	ignore:BRENDA::A0A0H3W5K4	ignore:BRENDA::I3VSF1

# Various L-lactate dehydrogenases are known, with different numbers of subunits; these all form pyruvate.
L-lactate-degradation: L-LDH

# A three-component L-lactate dehydrogenase LldEFG was described in Shewanella oneidensis
# (see PMID:19196979).
# A related system in Burkholderia phytofirmans PsJN is also required for L-lactate utilization;
# the lldEF subunits are quite similar but the lldG is diverged.
# LldE = SO_1520 or BPHYT_RS26975
lldE	L-lactate dehydrogenase, LldE subunit	uniprot:Q8EGS4	uniprot:B2TBW0
# LldF = SO_1519 or BPHYT_RS26970
lldF	L-lactate dehydrogenase, LldF subunit	uniprot:Q8EGS5	uniprot:B2TBY8
# LldG = SO_1518 or BPHYT_RS26965
lldG	L-lactate dehydrogenase, LldG subunit	uniprot:Q8EGS6	uniprot:B2TBY7
L-lactate-degradation: lldE lldF lldG

# A three-component L-lactate dehydrogenase LutABC was described in 
# Bacillus subtilis (PMC3347220, PMC2668416).
# Although LutABC does not seem to have been studied biochemically,
# it is required for L-lactate utilization, and induced during
# growth on L-lactate, and is distantly related to lldEFG.
# The related system from B. cereus has also been studied.
# Based on fitness data, similar systems were identified in
# Cupriavidus basilensis FW507-4G11 (lutA = RR42_RS21295; lutB = RR42_RS21285; lutC = RR42_RS21290)
# and Marinobacter adhaerens HP15 (lutA = HP15_4088, lutB = HP15_4089, lutC = HP15_4090).
lutA	L-lactate dehydrogenase, LutA subunit	curated:SwissProt::O07020	curated:SwissProt::Q81GA5	uniprot:A0A0C4YIN5	uniprot:E4PLR5
lutB	L-lactate dehydrogenase, LutB subunit	curated:SwissProt::O07021	curated:SwissProt::Q81GA4	uniprot:A0A0C4Y8G6	uniprot:E4PLR6
lutC	L-lactate dehydrogenase, LutC subunit	curated:SwissProt::O32259	curated:SwissProt::Q81GA3	uniprot:A0A0C4YFN9	uniprot:E4PLR7
L-lactate-degradation: lutA lutB lutC

# In Desulfovibrio vulgaris Hildenborough, a 2-component L-lactate dehydrogenase (DVU3032 and DVU3033) was identified
# (PMC4481167). Genome-wide fitness data did not identify any additional components.
# DVU3033 appears to be a fusion of lutA and lutB, and DVU3032 is distantly related to lutC
DVU3033	L-lactate dehydrogenase, fused LutA/LutB components	uniprot:Q726S3
DVU3032	L-lactate dehydrogenase, LutC-like component	uniprot:Q726S4
L-lactate-degradation: DVU3033 DVU3032

# L-lactate oxidase (EC 1.13.12.4, formerly 1.1.3.2) oxidizes L-lactate to acetate
# and CO2 under aerobic conditions. Some of these enzymes produce
# pyruvate (and hydroxgen peroxide) instead, but are still given this
# EC number. Either way, the acetate can be used for growth.
# However this enzyme is
# mostly found in fermentative bacteria, so its role could be
# to detoxify the accumulated lactate.
# Since L-lactate is a (S)-2-hydroxy-acid, ignore any similarities to
# (S)-2-hydroxy-acid oxidases (1.1.3.15)
lctO	L-lactate oxidase or 2-monooxygenase	EC:1.13.12.4	EC:1.1.3.2	ignore_other:1.1.3.15

# acetyl-CoA synthase or acetate kinase and phosphate acetyltransferase
import ethanol.steps:acs ackA pta

# Or, after L-lactate oxidase (lctO) forms acetate, the acetate is activated to acetyl-CoA.
L-lactate-degradation: lctO acs
L-lactate-degradation: lctO ackA pta

all: L-lactate-transport L-lactate-degradation

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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, 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

GapMind for catabolism of small carbon sources