Definition of L-phenylalanine catabolism

GapMind for catabolism of small carbon sources

Definition of L-phenylalanine catabolism

# Phenylalanine utilization in GapMind is based on MetaCyc pathway
# L-phenylalanine degradation I (aerobic, via tyrosine, metacyc:PHENYLALANINE-DEG1-PWY),
# pathway II (anaerobic, via phenylacetaldehyde dehydrogenase, metacyc:ANAPHENOXI-PWY),
# degradation via phenylpyruvate:ferredoxin oxidoreductase (PMC3346364),
# or degradation via phenylacetaldehyde:ferredoxin oxidoreductase (PMID:24214948).
# (MetaCyc describes additional pathways, but they do not result in carbon
# incorporation or are not reported in prokaryotes, so they are not included in GapMind.)

# In E. coli, the ABC transporter livFGHMJ or livFGHMK transports phenylalanine.
# livJ and livK are alternate substrate binding proteins that are similar to each other.
#
# A related system in Pseudomonas fluorescens FW300-N2E2 is also important for phenylalanine utlization:
#   Pf6N2E2_2921 = livK = A0A160A0J6; Pf6N2E2_2923 = livH = A0A0D9B2B6; Pf6N2E2_2924 = livM = A0A159ZYE0;
#    Pf6N2E2_2925 = livG = A0A159ZWS6; Pf6N2E2_2926 = livF = A0A159ZWL6).
#
# Ignored the orthologs in Pseudomonas aeruginosa (the bra system), which transports various
#   amino acids and might transport phenylalanine.
#
# A related system in Acidovorax sp. GW101-3H11 also transports phenylalanine:
#   LivF = Ac3H11_1692 (A0A165KC78), LivG = Ac3H11_1693 (A0A165KC86),
#   LivJ = Ac3H11_2396 (A0A165KTD4; not near the other components, but cofit),
#   LivH = Ac3H11_1695 (A0A165KC95), LivM = Ac3H11_1694 (A0A165KER0).

livF	L-phenylalanine ABC transporter, ATPase component 1 (LivF)	curated:CharProtDB::CH_003736	uniprot:A0A159ZWL6	ignore:TCDB::P21630	uniprot:A0A165KC78

livG	L-phenylalanine ABC transporter, ATPase component 2 (LivG)	curated:TCDB::P0A9S7	uniprot:A0A159ZWS6	ignore:TCDB::P21629	uniprot:A0A165KC86

livH	L-phenylalanine ABC transporter, permease component 1 (LivH)	curated:ecocyc::LIVH-MONOMER	uniprot:A0A0D9B2B6	ignore:TCDB::P21627	uniprot:A0A165KC95

livM	L-phenylalanine ABC transporter, permease component 2 (LivM)	curated:SwissProt::P22729	uniprot:A0A159ZYE0	ignore:TCDB::P21628	uniprot:A0A165KER0

livJ	L-phenylalanine ABC transporter, substrate-binding component LivJ/LivK	curated:CharProtDB::CH_107418	curated:TCDB::P0AD96	uniprot:A0A160A0J6	ignore:SwissProt::P21175	uniprot:A0A165KTD4

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

# RR42_RS33495 from Cupriavidus basilensis FW507-4G11 (A0A0C4YP23) is the phenylalanine transporter.
# Ignore A2RMP5, an ortholog from another Lactococcus.
aroP	L-phenylalanine:H+ symporter AroP	curated:TCDB::P15993	curated:TCDB::F2HN33	curated:TCDB::P24207	curated:TCDB::Q2VQZ4	curated:TCDB::Q46065	uniprot:A0A0C4YP23	ignore:SwissProt::A2RMP5

phenylalanine-transport: aroP

# non-specific eukaryotic transporters (i.e., Q01650) and the related serine/threonine exchanger SteT were excluded
# amino acid exporters such as yddG were excluded

# acetoacetate is an intermediate in tyrosine degradation
import leucine.steps:acetoacetate-degradation

# tyrosine is an intermediate in phenylalanine degradation
import tyrosine.steps:tyrosine-degradation

# phenylacetate is an intermediate in phenylalanine degradation
import phenylacetate.steps:phenylacetate-degradation phenylacetyl-CoA-degradation

# Several pathways involve transamination to phenylpyruvate
ARO8	L-phenylalanine transaminase	EC:2.6.1.1	EC:2.6.1.27	EC:2.6.1.57	ignore:BRENDA::Q845W8	ignore:BRENDA::A0A060PQX5	ignore:SwissProt::P52878	ignore:BRENDA::O57946

ARO10	phenylpyruvate decarboxylase	EC:4.1.1.43	ignore:BRENDA::A0A222AKA3

# The alpha subunit is MF179145 = A0A222AKA3 (which appears in BRENDA)
PPDCalpha	phenylpyruvate decarboxylase, alpha subunit	curated:BRENDA::A0A222AKA3
# The beta subunit is not curated but is MF179146 = ASO76824.1, identical in sequence to G1UHX5
PPDCbeta	phenylpyruvate decarboxylase, beta subunit	uniprot:G1UHX5

# Phenylpyruvate can be decarboxylated to phenylacetaldehyde by the typical
# homomeric enzyme, or by a heterodimer reported in Streptomyces virginiae
# (see PMID:28719183)
phenylpyruvate-decarboxylase: ARO10
phenylpyruvate-decarboxylase: PPDCalpha PPDCbeta

iorA	phenylpyruvate:ferredoxin oxidoreductase, IorA subunit	curated:BRENDA::O07835	curated:BRENDA::Q6LZB6	curated:BRENDA::Q6M0F5	curated:SwissProt::P80910

iorB	phenylpyruvate:ferredoxin oxidoreductase, IorB subunit	curated:BRENDA::O07836	curated:BRENDA::Q6LZB5	curated:BRENDA::Q6M0F6	curated:SwissProt::P80911

# A fused enzyme is described in Phaeobacter gallaeciensis (ior1 = A9ERV7 = I7EJ57, see PMC3346364).
iorAB	phenylpyruvate:ferredoxin oxidoreductase, fused IorA/IorB	curated:reanno::BFirm:BPHYT_RS02015	curated:reanno::Marino:GFF880	uniprot:I7EJ57

# This enzyme is usually known as
# indolepyruvate:ferredoxin oxidoreductase, but it acts on
# phenylpyruvate as well, forming phenylacetyl-CoA (PMID:8206994).
# Phenylpyruvate:ferredoxin oxidoreductase has both heterodimeric
# (iorA/iorB) and fused (iorAB) forms.
phenylpyruvate-fd-oxidoreductase: iorA iorB
phenylpyruvate-fd-oxidoreductase: iorAB

# Phenylalanine can be catabolized via transaminase ARO8, which forms
# phenylpyruvate (also known as 3-phenyl-2-oxo-propanoate),
# and phenylpyruvate:ferredoxin oxidoreductase, which forms
# phenylacetyl-CoA.
all: phenylalanine-transport ARO8 phenylpyruvate-fd-oxidoreductase phenylacetyl-CoA-degradation

pad-dh	phenylacetaldehyde dehydrogenase	EC:1.2.1.39

# In the anaerobic pathway, the transaminase ARO8 forms
# phenylpyruvate, a carboxy-lyase forms phenylacetaldehyde,
# and a dehydrogenase (pad-dh) forms phenylacetate
all: phenylalanine-transport ARO8 phenylpyruvate-decarboxylase pad-dh phenylacetate-degradation

# This enzyme is ebA5005 = Q5P143. It runs in parallel with a
# phenylacetaldehyde dehydrogenase (PMID:24214948).
pfor	phenylacetaldeyde:ferredoxin oxidoreductase	EC:1.2.7.5	uniprot:Q5P143

# Or, in a variation on the anaerobic pathway, the phenylacetaldehyde is oxidized to phenylacetate
# by phenylacetaldehyde:ferredoxin oxidoreductase (pfor).
all: phenylalanine-transport ARO8 phenylpyruvate-decarboxylase pfor phenylacetate-degradation

PAH	phenylalanine 4-monooxygenase	EC:1.14.16.1

PCBD	pterin-4-alpha-carbinoalamine dehydratase	EC:4.2.1.96

# In Pseudomonas, the cosubstrate of PAH is
# (6R)-L-threo-5,6,7,8-tetrahydroneopterin, also known as
# tetrahydromonapterin; in Chlorobaculum tepidum, it is
# (6R)-L-threo-5,6,7,8-tetrahydrobiopterin.
# EC:1.5.1.34 describes tetrahydrobiopterin reductases,
# while EC:1.5.1.50 describes bacterial dihydromonapterin reductases (folM in E. coli)
QDPR	6,7-dihydropteridine reductase	EC:1.5.1.34	EC:1.5.1.50	ignore:SwissProt::P26353	ignore:BRENDA::P15888	ignore:SwissProt::Q01234

# In the aerobic pathway, PAH forms tyrosine and hydroxylates its
# tetrahydropterin co-substrate; the tetrahydropterin is regenerated
# by dehydratase PCBD and reductase QDPR.
all: phenylalanine-transport PAH PCBD QDPR tyrosine-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:

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