Definition of L-tyrosine biosynthesis

GapMind for Amino acid biosynthesis

Definition of L-tyrosine biosynthesis

# Tyrosine biosynthesis in GapMind is based on MetaCyc pathways
# L-tyrosine biosynthesis I via 3-(4-hydroxyphenyl)pyruvate (metacyc:TYRSYN),
# pathway II via L-arogenate (metacyc:PWY-3461),
# pathway III via L-arogenate (metacyc:PWY-6120),
# or pathway IV via phenylalanine (metacyc:PWY-6134).
# Pathway II and III are identical except that different cofactors are used by
# L-arogenate dehydrogenase; these are not distinguished in GapMind.
# Pathways I and II/III both involve prephenate; in pathway I, prephenate is
# oxidized to hydroxyphenylpyruvate before being aminated, while in II/III, prephenate
# is aminated to arogenate before being oxidized to tyrosine.
# These alternatives are difficult to distinguish by sequence analysis.
# MetaCyc describes pathway IV as occuring in metazoa, but it
# also seems to be the main path to tyrosine in some aerobic bacteria
# (PMC7311316).

# MetaCyc tyrosine biosynthesis I

import phe.steps:cmutase ptransferase # chorismate mutase and prephenate aminotransferase

# prephenate dehydrogenase and arogenate dehydrogenase are difficult to distinguish.
# 1.3.1.12 and 1.3.1.13 vary by NAD(P)H cofactor.
# BT3933 (uniprot:Q8A0T8_BACTN), DVU0464 (uniprot:Q72EV4_DESVH), HSERO_RS18425 (uniprot:D8IR44_HERSS),
# and Ga0059261_2298 (uniprot:A0A1L6J750) are auxotrophic
# and have prephenate dehydrogenase domains (pfam:PF02153), but their specificity is unclear.
# HVO_1312 (uniprot:D4GXG3) is auxotrophic for tyrosine and is probably a prephenate dehydrogenase (PMC4300041).
# uniprot:P06959 is misannotated in BRENDA and is ignored.
# Ac3H11_2575 (uniprot:A0A162F6L0) has auxotrophic phenotypes but its specificity is unclear.
# uniprot:Q92MG1 was confirmed by binding tyrosine in a crystal structure (PDB:4wji).
# In Desulfarculus, the enzyme is a bit diverged (E1QE65), but has conserved tyrosine binding residues and
#  is in a conserved operon with aromatic amino acid biosynthesis genes.
pre-dehydr	prephenate dehydrogenase	EC:1.3.1.12	EC:1.3.1.13	uniprot:Q8A0T8_BACTN	curated:reanno::DvH:209400	uniprot:D8IR44_HERSS	uniprot:A0A1L6J750	ignore_other:EC 1.3.1.78	ignore_other:EC 1.3.1.43	ignore_other:EC 1.3.1.78	uniprot:D4GXG3	ignore:BRENDA::P06959	uniprot:Q92MG1	predicted:E1QE65

# The specificity of the aminotransferase is difficult to predict.
# Include EC:2.6.1.1 (aspartate amnotransferase) because it is reported to act on aromatic amino acids including tyrosine.
# uniprot:P12343 is a fragment.
# metacyc:MONOMER-15919 and metacyc:MONOMER-15918 are involved in phosphoserine formation and it is not clear if they
# would act on an aromatic amino acid.
# uniprot:H7CE71 appears to be misannotated in BRENDA and is ignored.
# uniprot:A0A060PQX5 and uniprot:Q845W8 are very similar to proteins with this activity, and might have
# this activity even though they are given other EC numbers, so similarity to them is ignored.
tyrB	tyrosine aminotransferase	EC:2.6.1.5	EC:2.6.1.27	EC:2.6.1.57	EC:2.6.1.1	ignore_other:EC 2.6.1.79	ignore_other:EC 2.6.1.78	ignore:SwissProt::P12343	ignore:metacyc::MONOMER-15919	ignore:metacyc::MONOMER-15918	ignore:BRENDA::H7CE71	ignore:BRENDA::A0A060PQX5	ignore:BRENDA::Q845W8

# Multiple EC numbers for varying use of NAD(P)H
# BT3933 and DVU0464 and HSERO_RS18425 are included but their specificity is uncertain
aro-dehydr	arogenate dehydrogenase	EC:1.3.1.78	EC:1.3.1.43	EC:1.3.1.78	uniprot:Q8A0T8_BACTN	curated:reanno::DvH:209400	uniprot:D8IR44_HERSS	uniprot:A0A1L6J750	ignore_other:EC 1.3.1.12	ignore_other:EC 1.3.1.13

# This enzyme requires oxygen
PAH	phenylalanine hydroxylase	EC:1.14.16.1

from-phe: PAH
all: cmutase pre-dehydr tyrB
all: cmutase ptransferase aro-dehydr
all: from-phe

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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