Definition of lactose catabolism

GapMind for catabolism of small carbon sources

Definition of lactose catabolism

# Lactose utilization in GapMind is based on
# MetaCyc pathway lactose degradation II via 3'-ketolactose (metacyc:LACTOSEUTIL-PWY),
# pathway III via beta-galactosidase (metacyc:BGALACT-PWY),
# or uptake by a PTS system followed by hydrolysis of lactose 6'-phosphate.
# (There is no pathway I.)

# ABC transporters:

# Agrobacterium radiobacter and Sinorhizobium meliloti have related systems,
# named lacEFGK in Agrobacterium
lacE	lactose ABC transporter, substrate-binding component	curated:TCDB::P29822	curated:reanno::Smeli:SM_b21652
lacF	lactose ABC transporter, permease component 1	curated:TCDB::P29823	curated:reanno::Smeli:SM_b21653
lacG	lactose ABC transporter, permease component 2	curated:TCDB::P29824	curated:reanno::Smeli:SM_b21654
lacK	lactose ABC transporter, ATPase component	curated:TCDB::Q01937	curated:reanno::Smeli:SM_b20002

# Transporters and PTS systems were identified using
# query: transporter:lactose:alpha-lactose:CPD-15971
lactose-transport: lacE lacF lacG lacK

# PTS systems:

lacIIA	lactose PTS system, EIIA component	curated:SwissProt::P0A0D6	curated:SwissProt::P11502	curated:SwissProt::P23532	curated:TCDB::Q045H4	curated:TCDB::Q045X4	curated:TCDB::U5MLJ3

lacIIB	lactose PTS system, EIIB component	curated:TCDB::U5MIE1

lacIIC	lactose PTS system, EIIC component	curated:TCDB::U5MFA1

lacIICB	lactose PTS system, fused EIIC and EIIB components	curated:SwissProt::P11162	curated:SwissProt::P23531	curated:SwissProt::P24400	curated:TCDB::Q045H3	curated:TCDB::Q045X3

# PTS systems forming lactose 6'-phosphate.
# Klebsiella pneumoniae has a EIIA,B,C in three separate proteins.
# The other characterized PTS systems have EIIA and EIICB
lactose-PTS: lacIIA lacIIB lacIIC
lactose-PTS: lacIIA lacIICB

# Homomeric transporters

lacP	lactose permease LacP	curated:CharProtDB::CH_124122	curated:CharProtDB::CH_124118	curated:CharProtDB::CH_124308	curated:CharProtDB::CH_124309	curated:TCDB::P07921
lactose-transport: lacP

lacS	lactose permease LacS	curated:SwissProt::Q7WTB2	curated:TCDB::P23936
lactose-transport: lacS

lacY	lactose:proton symporter LacY	curated:SwissProt::P02920	curated:SwissProt::P96517
lactose-transport: lacY

# Ignored sugar exporters such as setA or sotA

pbgal	phospho-beta-galactosidase	EC:3.2.1.85

import fructose.steps:tpi # part of galactose degradation
import galactose.steps:galactose-6-phosphate-degradation galactose-degradation

# LacACB from Caulobacter is the best studied lactose 3-dehydrogenase,
# but a related system from Pedobacter is also required for lactose utilization.
# EC:1.1.99.13 includes 3-ketoglycoside dehydrogenases more broadly.
# Other types of periplasmic 3-ketoglycoside dehydrogenases have been
# reported (ThuAB from Agrobacterium and Sinorhizobium and BT2158 from
# Bacteroides thetaiotaomicron) but these do not seem to be involved
# in lactose utilization.
# To avoid confusion with galactose catabolism genes, these are named
# lacA' etc. in GapMind.
lacA'	periplasmic lactose 3-dehydrogenase, LacA subunit	curated:reanno::Caulo:CCNA_01706	curated:reanno::Pedo557:CA265_RS15345	ignore_other: 1.1.99.13
lacC'	periplasmic lactose 3-dehydrogenase, LacC subunit	curated:reanno::Caulo:CCNA_01707	curated:reanno::Pedo557:CA265_RS15340	ignore_other: 1.1.99.13
lacB'	periplasmic lactose 3-dehydrogenase, cytochrome c component (LacB)	curated:reanno::Caulo:CCNA_01704	curated:reanno::Pedo557:CA265_RS15360	ignore_other: 1.1.99.13

# DUF1080 (PF06439) was recently identified
# as a family of 3-ketoglycoside hydrolases, and fitness data identified
# CCNA_01705 as the 3'-ketolactose hydrolase (PMID:33657378).
klh	periplasmic 3'-ketolactose hydrolase	curated:reanno::Caulo:CCNA_01705

# glk is glucokinase
import glucose.steps:glucose-utilization glk

lacL	heteromeric lactase, large subunit	curated:BRENDA::A0SWS3	curated:CAZy::AAA25267.1	curated:CAZy::AAL09167.1	curated:CAZy::ABF72116.1	curated:CAZy::ABJ65308.1	curated:CAZy::ACC38286.1	curated:CAZy::AEG39988.1	curated:CAZy::AEJ32720.1	curated:CAZy::BAA20536.1	curated:CAZy::CAA57730.1	curated:CAZy::CAD65569.1	curated:CAZy::CAZ66936.1	curated:SwissProt::Q7WTB4

lacM	heteromeric lactase, small subunit	curated:BRENDA::A0SWS4	curated:BRENDA::Q19R71	curated:SwissProt::Q7WTB3

# Mark the sequences for lacL or lacM as ignore, and also uniprot:BGAL_HORVU.
# Also mark some similar enzymes annotated as beta-glycosidases as ignore.
lacZ	lactase (homomeric)	EC:3.2.1.108	EC:3.2.1.23	ignore:BRENDA::A0SWS3	ignore:CAZy::AAA25267.1	ignore:CAZy::AAL09167.1	ignore:CAZy::ABF72116.1	ignore:CAZy::ABJ65308.1	ignore:CAZy::ACC38286.1	ignore:CAZy::AEG39988.1	ignore:CAZy::AEJ32720.1	ignore:CAZy::BAA20536.1	ignore:CAZy::CAA57730.1	ignore:CAZy::CAD65569.1	ignore:CAZy::CAZ66936.1	ignore:SwissProt::Q7WTB4	ignore:BRENDA::A0SWS4	ignore:BRENDA::Q19R71	ignore:SwissProt::Q7WTB3	ignore:SwissProt::P83252	ignore:CAZy::AAA79030.1	ignore:CAZy::AAN05439.1	ignore:CAZy::AAF36392.1	ignore:CAZy::AAN05441.1	ignore:CAZy::ABW87307.1	ignore:CAZy::AAO15361.1	ignore:CAZy::AAN05440.1	ignore:CAZy::ABW01253.1	ignore:CAZy::AAY81155.1	ignore:CAZy::CAA34074.1	ignore:CAZy::ADL19795.1	ignore:CAZy::AEE47485.1	ignore:CAZy::ACK41548.1	ignore:CAZy::ABX04075.1	ignore:CAZy::BAA78713.1	ignore:BRENDA::Q8DR24

# Most lactases are homomeric, but Lactobacillus have a heteromeric enzyme LacLM.
# (There is also a heteromeric beta-galactosidase in barley, see uniprot:BGAL_HORVU, but it is not included.
#  Also, "evolved beta-galactosidase" ebgA from E. coli is more active with its partner ebgC,
#  but it retains activity on its own, so it is included in step lacZ instead.)
beta-galactosidase: lacZ
beta-galactosidase: lacL lacM

# In pathway III, lactose is taken up and cleaved to galactose and glucose by beta-galactosidase;
# the glucose is consumed by kinase glk.
# (The galactose 1-epimerase galM, EC:5.1.3.3, is not included in galactose degradation;
#  it is important for lactose utilization in E. coli (PMID:7966338), but
#  not in Sinorhizobium meliloti or in Bacteroides thetaiotaomicron, which also
#  use this pathway.)
all: lactose-transport beta-galactosidase galactose-degradation glk

# Or, a PTS forms lactose 6'-phosphate and phosphogalactosidase (pbgal)
# forms galactose 6-phosphate and glucose.
all: lactose-PTS pbgal galactose-6-phosphate-degradation glk

# Or, lactose is oxidized to 3'-ketolactose by a periplasmic
# 3-component dehydrogenase (lacACB'), and then hydrolyzed by a
# periplasmic enzyme (klh) to 3-keto-beta-D-galactose and
# D-glucopyranose, and hypothetical reduction of the
# 3-ketogalactose. Liberation of glucose is probably sufficient for
# growth.
all: lacA' lacC' lacB' klh glucose-utilization

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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

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