GapMind for catabolism of small carbon sources


Definition of L-leucine catabolism

As text, or see rules and steps

# Leucine degradation in GapMind is based on MetaCyc pathway L-leucine degradation I,
# via branched alpha-keto acid dehydrogenase (metacyc:LEU-DEG2-PWY).
# Other pathways for are not included here because they are not linked to sequence
# (metacyc:PWY-5075) or do not result in carbon incorporation.

# ABC transporters:

# E. coli livFGHMJ or livFGHMK (livK and livJ are alternate SBPs);
#   and livJFGHM from Streptococcus pneumoniae;
#   and braCDEFG from Pseudomonas aeruginosa (braC is the SBP);
#   and braDEFG/braC3 from R. leguminosarum; braC3 (RL3540; Q1MDE9) is a secondary
#     SBP that transports leucine/isoleucine/valine/alanine (PMID:19597156); the
#     proximal braC (Q9L3M3) is also thought to be involved in leucine transport (PMC135202);
#   LivH/BraD = RL3750/Q1MCU0; LivM/BraE = RL3749/Q1MCU1;
#   LivG/BraF = RL3748/Q1MCU2; LivF/BraG = RL3747/Q1MCU3;
#   and in Acidovorax sp. GW101-3H11:
#   LivF = Ac3H11_1692 (A0A165KC78), LivG = Ac3H11_1693 (A0A165KC86),
#   LivJ = Ac3H11_2396 (A0A165KTD4; not near the other components, but strong phenotype on leucine and cofitness),
#   LivH = Ac3H11_1695 (A0A165KC95), LivM = Ac3H11_1694 (A0A165KER0);
livF	L-leucine ABC transporter, ATPase component 1 (LivF/BraG)	curated:CharProtDB::CH_003736	curated:TCDB::P21630	curated:TCDB::Q8DQH7	uniprot:Q1MCU3	uniprot:A0A165KC78

livG	L-leucine ABC transporter, ATPase component 2 (LivG/BraF)	curated:TCDB::P0A9S7	curated:TCDB::P21629	curated:TCDB::Q8DQH8	uniprot:Q1MCU2	uniprot:A0A165KC86

livJ	L-leucine ABC transporter, substrate-binding component (LivJ/LivK/BraC/BraC3)	curated:SwissProt::P21175	curated:CharProtDB::CH_107418	curated:TCDB::P0AD96	curated:TCDB::Q8DQI1	uniprot:Q1MDE9	curated:TCDB::Q9L3M3	uniprot:A0A165KTD4

livH	L-leucine ABC transporter, permease component 1 (LivH/BraD)	curated:TCDB::P21627	curated:TCDB::Q8DQI0	curated:ecocyc::LIVH-MONOMER	uniprot:Q1MCU0	uniprot:A0A165KC95

# LivM from Streptococcus pneumoniae lacks an N-terminal domain of unknown
# function (DUF3382) that is found in E.coli and P. aeruginosa
livM	L-leucine ABC transporter, permease component 2 (LivM/BraE)	curated:SwissProt::P22729	curated:TCDB::P21628	curated:TCDB::Q8DQH9	uniprot:Q1MCU1	uniprot:A0A165KER0

# Transporters were identified using
# query: transporter:leucine:L-leucine
leucine-transport: livF livG livJ livH livM

# Synechocystis natABCDE and a related system in Anabaena (annotated with "leu" not leucine as the substrate)
natA	L-leucine ABC transporter, ATPase component 1 (NatA)	curated:TCDB::Q55164	curated:TCDB::Q7A2H0
natB	L-leucine ABC transporter, substrate-binding component NatB	curated:TCDB::Q55387	curated:TCDB::Q8YVY4
natC	L-leucine ABC transporter, permease component 1 (NatC)	curated:TCDB::P74455	curated:TCDB::Q8YY08
natD	L-leucine ABC transporter, permease component 2 (NatD)	curated:TCDB::P74318	curated:TCDB::Q8YXD0
natE	L-leucine ABC transporter, ATPase component 2 (NatE)	curated:TCDB::P73650	curated:TCDB::Q8YT15
leucine-transport: natA natB natC natD natE

# AapJQMP from Rhizobium leguminosarum is described in glutamate.steps
import glutamate.steps:aapJ aapQ aapM aapP
leucine-transport: aapJ aapQ aapM aapP

# Homomeric transporters:

leuT	L-leucine:Na+ symporter LeuT	curated:TCDB::O67854
leucine-transport: leuT

brnQ	L-leucine:Na+ symporter BrnQ/BraB	curated:TCDB::P0AD99	curated:TCDB::P19072
leucine-transport: brnQ

bcaP	L-leucine uptake transporter BcaP	curated:TCDB::S6EX81
leucine-transport: bcaP

Bap2	L-leucine permease Bap2	curated:CharProtDB::CH_091448	curated:TCDB::Q2VQZ4
leucine-transport: Bap2

AAP1	L-leucine permease AAP1	curated:CharProtDB::CH_091601
leucine-transport: AAP1

# Ignore heteromeric systems found only in animals (i.e., TC 2.A.3.8.25)
# Ignore regulatory proteins such as SC16B_HUMAN, SSY1_YEAST
# Ignore amino acid exporters such as leuE, yjeH, brnEF

# These enzymes transfer the amino group to 2-oxoglutarate to form
# glutamate; glutamate dehydrogenase (not included in the pathway
# definition) can then release the ammonia. Many other paths are
# possible but do not seem to be known (i.e., transfer to oxaloacetate
# followed by aspartate-ammonia lyase).
ilvE	L-leucine transaminase	EC:	EC:

bkdA	branched-chain alpha-ketoacid dehydrogenase, E1 component alpha subunit	curated:SwissProt::P12694	curated:BRENDA::Q72GU1	curated:CharProtDB::CH_121278	curated:SwissProt::O45924	curated:SwissProt::P11178	curated:SwissProt::P9WIS3	curated:SwissProt::Q5SLR4	curated:SwissProt::Q84JL2	curated:SwissProt::Q9LPL5	curated:reanno::Smeli:SMc03201	curated:reanno::pseudo13_GW456_L13:PfGW456L13_3540	curated:reanno::pseudo3_N2E3:AO353_26635	curated:reanno::pseudo5_N2C3_1:AO356_22990	curated:reanno::pseudo6_N2E2:Pf6N2E2_481	curated:metacyc::MONOMER-11683

bkdB	branched-chain alpha-ketoacid dehydrogenase, E1 component beta subunit	curated:CharProtDB::CH_121283	curated:SwissProt::P21953	curated:SwissProt::P9WIS1	curated:SwissProt::Q5SLR3	curated:SwissProt::Q9LDY2	curated:metacyc::MONOMER-11684	curated:reanno::Smeli:SMc03202	curated:reanno::WCS417:GFF3430	curated:reanno::pseudo13_GW456_L13:PfGW456L13_3541	curated:reanno::pseudo5_N2C3_1:AO356_22985	curated:reanno::pseudo6_N2E2:Pf6N2E2_480	curated:BRENDA::Q9HIA4

bkdC	branched-chain alpha-ketoacid dehydrogenase, E2 component	EC:

lpd	branched-chain alpha-ketoacid dehydrogenase, E3 component	EC:

vorA	branched-chain alpha-ketoacid:ferredoxin oxidoreductase, alpha subunit VorA	curated:SwissProt::P80907	ignore_other:
vorB	branched-chain alpha-ketoacid:ferredoxin oxidoreductase, beta subunit VorB	curated:SwissProt::P80908	ignore_other:
vorC	branched-chain alpha-ketoacid:ferredoxin oxidoreductase, gamma subunit VorC	curated:SwissProt::P80909	ignore_other:

# ofoAB is similar to low-specificity 2-oxoacid oxidoreductases (EC:; it is generally
# not certain if these act on 4-methyl-2-oxopentanoate or not, but they probably do.
ofoA	branched-chain alpha-ketoacid:ferredoxin oxidoreductase, alpha subunit OfoA	curated:SwissProt::P72578	ignore_other:	ignore_other:

ofoB	branched-chain alpha-ketoacid:ferredoxin oxidoreductase, beta subunit OfoB	curated:SwissProt::P72579	ignore_other:	ignore_other:

ofo	branched-chain alpha-ketoacid:ferredoxin oxidoreductase, fused	curated:reanno::Cup4G11:RR42_RS19540	curated:reanno::psRCH2:GFF3452	ignore_other:	ignore_other:

# These decarboxylating dehydrogenases act on
# 4-methyl-2-oxopentanoate,
# 3-methyl-2-oxobutanoate (2-oxoisovalerate)
# and (S)-3-methyl-2-oxopentanoate and are known as the branched-chain
# alpha-ketoacid dehydrogenases.
# They can pass electrons to NAD (EC: or to ferredoxin (EC:
# The NAD-dependent enzyme is the sum of three activities:
# EC: (the 4-methyl-2-oxopentanoate dehydrogenase, with transfer to the lipopoyllysine residue of
#   which is itself heteromeric, with alpha and beta subunits;
# EC: (dihydrolipoyllysine-residue (3-methylbutanoyl)transferase);
# and EC: (dihydrolipoyl dehydrogenase, transferring electrons to NAD).
BKD: bkdA bkdB bkdC lpd
# The well-characterized ferredoxin-dependent enzymes have 3 subunits (vorABC) or 2 subunits (ofoAB).
BKD: vorA vorB vorC
BKD: ofoA ofoB
# Genetic data identified a fused ferredoxin-dependent enzyme with just 1 subunit (ofo).
BKD: ofo

liuA	isovaleryl-CoA dehydrogenase	EC:	EC:

# 3-methylcrotonyl-CoA carboxylase has 2 subunits
liuB	3-methylcrotonyl-CoA carboxylase, alpha (biotin-containing) subunit	curated:CharProtDB::CH_122249	curated:BRENDA::Q42523	curated:BRENDA::Q9I299	curated:SwissProt::Q2QMG2	curated:SwissProt::Q96RQ3	curated:SwissProt::Q99MR8	curated:reanno::SB2B:6937189	curated:reanno::Smeli:SM_b21124	curated:reanno::pseudo1_N1B4:Pf1N1B4_3984	curated:reanno::pseudo5_N2C3_1:AO356_01595	curated:reanno::pseudo6_N2E2:Pf6N2E2_2194	ignore_other:
liuD	3-methylcrotonyl-CoA carboxylase, beta subunit	curated:BRENDA::Q9I297	curated:BRENDA::Q9LDD8	curated:CharProtDB::CH_122289	curated:SwissProt::Q9HCC0	curated:SwissProt::Q9V9A7	curated:reanno::SB2B:6937191	curated:reanno::Smeli:SM_b21122	curated:reanno::psRCH2:GFF1050	curated:reanno::pseudo5_N2C3_1:AO356_01585	curated:reanno::pseudo6_N2E2:Pf6N2E2_2192	ignore_other:

# SM_b21126 (Q92VJ6) is a bit diverged and is confirmed by fitness data
liuC	3-methylglutaconyl-CoA hydratase	EC:	uniprot:Q92VJ6

liuE	hydroxymethylglutaryl-CoA lyase	EC:

atoA	acetoacetyl-CoA transferase, A subunit	curated:ecocyc::ATOD-MONOMER	curated:metacyc::HP0691-MONOMER	curated:reanno::psRCH2:GFF1045	curated:reanno::pseudo6_N2E2:Pf6N2E2_2111	ignore_other:

atoD	acetoacetyl-CoA transferase, B subunit	curated:ecocyc::ATOA-MONOMER	curated:metacyc::HP0692-MONOMER	curated:reanno::psRCH2:GFF1044	curated:reanno::pseudo6_N2E2:Pf6N2E2_2112	ignore_other:

aacS	acetoacetyl-CoA synthetase	EC:

# acetyl-CoA:acetoacetyl-CoA transferase (sometimes given EC: or EC:
# or succinyl-CoA:acetoacetyl-CoA transferase (EC:, also known as 3-oxoacid CoA-transferase)
# can activate acetoacetate.
# These have an A and B subunit.
acetoacetate-activation: atoA atoD
# Alternatively, an ATP-dependent ligase (aacS) can activate acetoacetate (EC:
acetoacetate-activation: aacS

# Produces two acetyl-CoA from acetoacetyl-CoA and CoA.
# EC: describes a broader range of beta-ketothiolases.
# This enzyme is usually homomeric, but uniprot:I3R3D0 and uniprot:I3RA71 are non-catalytic subunits
# of an enzyme from Haloferax mediterranei that also contains a
# "normal" catalytic subunit (uniprot:I3R3D1, uniprot:I3RA72).
# Inclusion of uniprot:P07256 was an error in BRENDA.
# And CharProtDB includes an odd annotation of the form "similar to acetyl-CoA acetyltransferase"
atoB	acetyl-CoA C-acetyltransferase	EC:	ignore_other:	ignore:BRENDA::P07256	ignore:BRENDA::I3R3D0	ignore:BRENDA::I3RA71	ignore_other:similar to acetyl-CoA acetyltransferase

# The acetoacetate is activated to acetoacetyl-CoA,
# and cleaved by acetyl-CoA acetyltransferase,
# giving two acetyl-CoA.
acetoacetate-degradation: acetoacetate-activation atoB

# After transamination to 4-methyl-2-oxopentanoate by ilvE,
# kbd oxidatively decarboxylates it to isovaleryl-CoA (also known as 3-methylbutanoyl-CoA),
# liuA oxidizes it to 3-methylcrotonyl-CoA,
# liuBD carboxylates it to 3-methylglutaconyl-CoA,
# liuC hydrates it to hydroxymethylglutaryl-CoA,
# and liuE hydrolyzes it to acetoacetate and acetyl-CoA.
all: leucine-transport ilvE BKD liuA liuB liuD liuC liuE acetoacetate-degradation



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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 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