Definition of L-leucine biosynthesis

GapMind for Amino acid biosynthesis

Definition of L-leucine biosynthesis

# Leucine biosynthesis in GapMind is based on MetaCyc pathway L-leucine biosynthesis (metacyc:LEUSYN-PWY).
# This begins with the initial steps of
# valine biosynthesis (see metacyc:VALSYN-PWY), up to 3-methyloxobutanoate.

import val.steps:3-methyl-2-oxobutanoate
import ile.steps:leuB leuC leuD

# Ignore CharProtDB entries with no EC number.
# Add Echvi_3833 (uniprot:L0G5E1_ECHVK) and CA265_RS15855 (uniprot:A0A1X9Z750_9SPHI), which are supported by fitness data.
# uniprot:P85362 is ignored because it is just 9 amino acids.
# uniprot:S3D9F8 and uniprot:K0E4E5 are involved in secondary metabolite synthesis and it is not
# clear if they actually have this activity, so they are ignored.
leuA	2-isopropylmalate synthase	EC:2.3.3.13	uniprot:L0G5E1_ECHVK	uniprot:A0A1X9Z750_9SPHI	ignore_other:isopropylmalate synthase	ignore:SwissProt::P85362	ignore:SwissProt::S3D9F8	ignore:SwissProt::K0E4E5

# Q8NS92 is ignored because it is primarily a transcriptional regulator.
# Similarity to aromatic amino acid transaminases or tyrosine transaminases is ignored as they
# are often non-specific.
ilvE	leucine transaminase	EC:2.6.1.6	EC:2.6.1.42	ignore:SwissProt::Q8NS92	ignore_other:2.6.1.57	ignore_other:2.6.1.5

all: 3-methyl-2-oxobutanoate leuA leuC leuD leuB ilvE

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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