Definition of L-phenylalanine biosynthesis

GapMind for Amino acid biosynthesis

Definition of L-phenylalanine biosynthesis

# Phenylalanine biosynthesis in GapMind is based on MetaCyc pathways
# L-phenylalanine biosynthesis I (metacyc:PHESYN),
# II (metacyc:PWY-3462), and III (metacyc:PWY-7432).
# Pathways I and III proceed via 3-phenyl-2-oxopropanoate, but with different
# amino acids providing the amino group for the conversion to phenylalanine.
# In pathway II, L-arogenate is the intermediate (the aminotransferase reaction occurs before the dehydratase reaction).

# These enzymes are usually annotated as aromatic-amino-acid transaminase, but only
# the activity on phenylpyruvate (to form phenylalanine) is relevant here.
# Phenylalanine is also considered a substrate for aspartate aminotransferases,
# uniprot:P39643 is annotated with this EC number but is involved in bacilysin biosynthesis and
# probably wouldn't form phenylalanine.
# uniprot:H7CE71 is misannotated as this in BRENDA.
# metacyc:PHETRANTHAUERA-MONOMER has this activity but is annotated with a different EC number.
# uniprot:A0A060PQX5 has this activity but is given a different EC number in BRENDA.
# metacyc:MONOMER-15918 and uniprot:Q93QX0 probably do not have this activity.
# Many branched-chain or tryptophan transaminases are also active on phenylalanine so any similarity to them is ignored.
# Ignore the very short protein uniprot:P12343
PPYAT phenylpyruvate aminotransferase EC:2.6.1.57 EC:2.6.1.1 EC:2.6.1.5 ignore:SwissProt::P39643 ignore:BRENDA::H7CE71 curated:metacyc::PHETRANTHAUERA-MONOMER curated:BRENDA::A0A060PQX5 ignore_other:EC 2.6.1.27 ignore_other:2.6.1.42 ignore:SwissProt::P12343 ignore:metacyc::MONOMER-15918 ignore:SwissProt::Q93QX0

# Chorismate mutase is usually fused to prephenate dehydratase, which
# makes it difficult to find this activity when it is fused to something else, so
# we included the entire pfam in the step's definition.
# The only other function for this family that we are aware of is
# 4-amino-4-deoxychorismate mutase, which is involved in the biosynthesis of some antibiotics.
# (Proteins that are similar to 4-amino-4-deoxychorismate mutases will be marked as medium-confidence
# in the results.)
# Several fusion proteins are missing this EC number in their annotations
# (uniprot:P43902, uniprot:Q74NC4, uniprot:A8AAX2)
cmutase chorismate mutase EC:5.4.99.5 hmm:PF01817 curated:BRENDA::P43902 curated:BRENDA::Q74NC4 curated:BRENDA::A8AAX2

# prephenate dehydratase and arogenate dehydratase can be difficult to distinguish.
# BT3936 (uniprot:Q8A0T5_BACTN) is diverged but has auxotrophic phenotypes (as do homologs Echvi_0123, CA265_RS11630).
# HVO_0449 (uniprot:D4GRZ0) is a phenylalanine auxotroph and is probably prephenate dehydratase (PMC4300041).
# uniprot:A0A160HWY7 from Brevundimonas is a somewhat diverged prephenate dehydratase; it has auxotrophic phenotypes.
# The putative prephenate dehydratase from Carboxydothermus pertinax (A0A1L8CUL6) is lacking
# the regulatory (ACT) domain but has the active site residues and is often encoded near aromatic amino
# acid synthesis genes (it might be an arogenate dehydratase instead).
preph-dehydratase prephenate dehydratase EC:4.2.1.51 uniprot:Q8A0T5_BACTN ignore_other:EC 4.2.1.91 uniprot:D4GRZ0 uniprot:A0A160HWY7 predicted:A0A1L8CUL6

# This enzyme forms arogenate, also known as pretyrosine.
# Similarity to uniprot:O50434 is ignored because it is not acutally characterized.
ptransferase prephenate aminotransferase EC:2.6.1.79 EC:2.6.1.78 ignore_other:EC 2.6.1.5 ignore_other:EC 2.6.1.27 ignore_other:EC 2.6.1.57 ignore_other:EC 2.6.1.1 ignore:SwissProt::O50434

aro-dehydratase arogenate dehydratase EC:4.2.1.91 ignore_other:EC 4.2.1.51

all: cmutase ptransferase aro-dehydratase
all: cmutase preph-dehydratase PPYAT

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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