As text, or see rules and steps
# Lysine degradation in GapMind is based on many metacyc pathways # (metacyc:PWY-5327), including # L-lysine degradation I via cadaverine (metacyc:PWY0-461), # pathway IV via lysine monooxygenase (metacyc:PWY-5280), # pathway V via D-lysine (metacyc:PWY-5283), # pathway VI via lysine 6-aminotransferase (metacyc:PWY-5298), # pathway VIII via lysine 6-dehydrogenase (metacyc:PWY-5314), # and fermentation to acetate and butanoate (metacyc:P163-PWY). # Pathway X (metacyc:PWY-6328) is similar to pathway I (with cadaverine and glutarate as intermediates), but # glutarate is consumed via glutaryl-CoA (as in pathway IV); # it does not introduce any new steps. # Pathways II (L-pipecolate pathway) # and III (via N6-acetyllysine) # and VII (via 6-amino-2-oxohexanoate) # and IX (similar to pathway IV) # and XI (via saccharopine) # are not thought to occur in prokaryotes and are not included in GapMind. lysP L-lysine:H+ symporter LysP curated:CharProtDB::CH_003129 curated:CharProtDB::CH_091040 curated:CharProtDB::CH_091257 curated:CharProtDB::CH_091412 curated:SwissProt::A0A1D8PPG4 curated:SwissProt::A0A1D8PPI5 curated:SwissProt::A2RNZ6 curated:SwissProt::Q59WU0 curated:TCDB::K7VV21 curated:TCDB::P43059 # Transporters were identified using # query: transporter:lysine:L-lysine:lys:L-lys lysine-transport: lysP LHT L-lysine transporter curated:SwissProt::Q9FKS8 curated:SwissProt::Q9LRB5 curated:SwissProt::Q9SX98 curated:TCDB::Q84WE9 lysine-transport: LHT Slc7a1 L-lysine transporter Slc7a1 curated:CharProtDB::CH_091036 curated:CharProtDB::CH_091271 curated:CharProtDB::CH_091324 lysine-transport: Slc7a1 lysL L-lysine transporter LysL curated:CharProtDB::CH_019644 lysine-transport: lysL # In E. coli and Salmonella, the ABC transporter has a lysine/arginine specific binding protein (argT), # two permease subunits (hisQM, which are similar to each other), and an ATPase subunit (hisP). # Pseudomonas aeruginosa has a homologous lysine transporter, PA5152-PA5155, # as do various strains of Pseudomonas fluorescens. # In P. putida, a similar system was identified using fitness data # (argT = PP_3593 = Q88GX4; hisQ = PP_3594 = Q88GX3; hisM = PP_3595 = Q88GX2; hisP = PP_3597 = Q88GX0). # In S. meliloti, a similar substrate-binding protein was identified using fitness data (SMc00140 = Q92PA9), # but the ATPase subunit was not found (it might be shared with other systems). argT L-lysine ABC transporter, substrate-binding component ArgT curated:CharProtDB::CH_003045 curated:TCDB::P09551 curated:TCDB::Q9HU31 curated:reanno::pseudo5_N2C3_1:AO356_05495 curated:reanno::pseudo5_N2C3_1:AO356_09900 curated:reanno::pseudo6_N2E2:Pf6N2E2_2958 uniprot:Q92PA9 uniprot:Q88GX4 hisM L-lysine ABC transporter, permease component 1 (HisM) curated:SwissProt::P0A2I7 curated:SwissProt::P0AEU3 curated:TCDB::Q9HU29 curated:reanno::pseudo5_N2C3_1:AO356_05505 curated:reanno::pseudo5_N2C3_1:AO356_09910 curated:reanno::pseudo6_N2E2:Pf6N2E2_2960 uniprot:Q88GX2 hisQ L-lysine ABC transporter, permease component 2 (HisQ) curated:SwissProt::P0A2I9 curated:SwissProt::P52094 curated:TCDB::Q9HU30 curated:reanno::pseudo5_N2C3_1:AO356_05500 curated:reanno::pseudo5_N2C3_1:AO356_09905 curated:reanno::pseudo6_N2E2:Pf6N2E2_2959 uniprot:Q88GX3 hisP L-lysine ABC transporter, ATPase component HisP curated:CharProtDB::CH_003210 curated:SwissProt::P02915 curated:TCDB::P73721 curated:TCDB::Q9HU32 curated:reanno::pseudo5_N2C3_1:AO356_05515 curated:reanno::pseudo5_N2C3_1:AO356_09895 curated:reanno::pseudo6_N2E2:Pf6N2E2_2962 uniprot:Q88GX0 lysine-transport: argT hisM hisQ hisP # In Synechocystis, there is just one permease component fused to the # substrate-binding component. The fusion protein is known as BgtB or BgtAB; # BgtA is the hisP-like ATPase component. bgtB L-histidine ABC transporter, fused substrate-binding and permease components (BgtB/BgtAB) curated:TCDB::P73544 curated:TCDB::Q8YSA2 lysine-transport: bgtB hisP # Lysine exporters (LysE), porins, lysine:cadaverine antiporters # (cadB), vacuolar transporters, lysosomal transporters, mitochondrial # carrier proteins, and the schistosome amino acid transporter (TC # 2.A.3.8.3) were excluded. import leucine.steps:atoB # acetyl-CoA acetyltransferase is part of glutaryl-CoA degradation import phenylacetate.steps:glutaryl-CoA-degradation glaH glutarate 2-hydroxylase, succinate-releasing (GlaH or CsiD) EC:1.14.11.64 # As discussed in the MetaCyc page for lhgO (G1G01-3089-MONOMER), # there is some controversy as to whether the E. coli enzyme (lhgD) # uses quinone or oxygen as its acceptor; the Pseudomonas protein # (G1G01-3089-MONOMER) does use oxygen. lhgD L-2-hydroxyglutarate dehydrogenase or oxidase (LhgD or LhgO) EC:1.1.5.13 curated:metacyc::G1G01-3089-MONOMER EC:1.1.99.2 # Glutarate is an intermediate in L-lysine degradation. As part of # MetaCyc pathway L-lysine degradation I (metacyc:PWY0-461), gluratate is hydroxylated # to L-2-hydroxyglutarate (also known as (S)-2-hydroxyglutarate) by a # 2-oxoglutarate-dependent oxidase. This reaction releases succinate # (a TCA cycle intermediate) and CO2. A dehydrogenase then oxidizes to # L-2-hydroxyglutarate to regenerate 2-oxoglutarate. glutarate-degradation: glaH lhgD gcdG succinyl-CoA:glutarate CoA-transferase EC:2.8.3.13 # Alternatively, as part of pathway IV (metacyc:PWY-5280), # glutarate can be activated to glutaryl-CoA by a # CoA-transferase. Glutaryl-CoA degradation (metacyc:PWY-5177) # involves glutaryl-CoA dehydrogenase # (decarboxylating) to crotonyl-CoA (trans-but-2-enoyl-CoA), hydration # to (S)-hydroxybutanoyl-CoA, oxidization to acetoacetyl-CoA, and cleavage # by a C-acetyltransferase to two acetyl-CoA. glutarate-degradation: gcdG glutaryl-CoA-degradation # Ignore some very-similar 4-aminobutyrate transaminases davT 5-aminovalerate aminotransferase EC:2.6.1.48 ignore:metacyc::MONOMER-11537 ignore:BRENDA::Q0K2K2 # Ignore some very-similar succinate-semialdehyde dehydrogenases davD glutarate semialdehyde dehydrogenase EC:1.2.1.20 ignore:reanno::pseudo3_N2E3:AO353_11505 ignore:metacyc::MONOMER-15736 curated:SwissProt::Q9I6M5 ignore:BRENDA::P25526 ignore:metacyc::MONOMER-20455 ignore:reanno::MR1:200453 # 5-aminovalerate is an intermediate in L-lysine degradation (metacyc:PWY0-461, metacyc:PWY-5280). # It is transaminated to glutarate semialdehyde and oxidized to glutarate. # (A fermentative pathway via 5-hydroxyvalerate has also been reported, but # does not seem to be fully linked to sequence; see pathway 5 of PMID:11759672.) 5-aminovalerate-degradation: davT davD glutarate-degradation # Q06191 is very similar to SMc04386 (P58350), which is specifically important for lysine # utilization. lysN 2-aminoadipate transaminase EC:2.6.1.39 ignore:SwissProt::Q06191 # PP_5260 was shown to be form D-2-hydroxyglutarate (URL:https://doi.org/10.1101/450254). # Homologous proteins that are specifically important for L-lysine utilization are # also included. The E. coli homolog (ydcJ, G6738-MONOMER) also has this activity, # see PMC7286885. hglS D-2-hydroxyglutarate synthase curated:reanno::Putida:PP_5260 curated:reanno::pseudo5_N2C3_1:AO356_01105 curated:reanno::Smeli:SMc04383 curated:ecocyc::G6738-MONOMER # PP_4493 was misannotated as EC 1.1.3.15, which acts on (S)-2-hydroxyglutarate. # The E. coli homolog (ydiJ, ecocyc:G6913-MONOMER) does not seem to be characterized. # SMc04384 (Q92L08) was identified using fitness data. ydiJ (R)-2-hydroxyglutarate dehydrogenase EC:1.1.99.39 EC:1.1.99.40 curated:reanno::Putida:PP_4493 uniprot:Q92L08 # L-2-aminoadipate is an intermediate in L-lysine degradation # pathways V and VI (metacyc:PWY-5283, metacyc:PWY-5298). # A transaminase forms 2-oxoadipate, a oxygenase/decarboxylase # (D-2-hydroxyglutarate synthase) forms (R)-2-hydroxyglutarate, and a # dehydrogenase forms 2-oxoglutarate, which is an intermediate in the # TCA cycle. L-2-aminoadipate-degradation: lysN hglS ydiJ # A0A0H3H393 is very similar to E. coli diaminopimelate decarboxylase # and could not access the paper about it, so do not trust it. cadA lysine decarboxylase EC:4.1.1.18 ignore:BRENDA::A0A0H3H393 # E. coli's putrescine aminotransferase (patA) is known to carry out # this reaction as well. I could not identify any evidence of other # proteins that carry out this reaction (although it seems likely that # other putrescine aminotransferases could). patA cadaverine aminotransferase curated:metacyc::G7596-MONOMER # E. coli 4-aminobutanal dehydrogenase (patD, P77674) is known to # carry out this reaction. It seems likely that other members of # EC:1.2.1.19 (4-aminobutanal dehydrogenase) would perform it as well. patD 5-aminopentanal dehydrogenase curated:SwissProt::P77674 ignore_other:1.2.1.19 # In pathway I, lysine is decarboxylated by cadA to cadaverine (1,5-diaminopentane), transaminated # to 5-aminopentanal by patA, and oxidized to 5-aminovalerate by patD. all: lysine-transport cadA patA patD 5-aminovalerate-degradation davB L-lysine 2-monooxygenase EC:1.13.12.2 davA 5-aminovaleramidase EC:3.5.1.30 # In pathway IV, the monooxygenase/decarboxylase davB forms # 5-aminopentanamide, which is hydrolyzed to 5-aminovalerate # (5-aminopentanoate). all: lysine-transport davB davA 5-aminovalerate-degradation # Some lysine racemases are very similar to broad-specificity amino # acid racemases (EC 5.1.1.10) alr lysine racemase EC:5.1.1.5 ignore_other:5.1.1.10 # The ribosomal protein P80340 is misannotated in BRENDA amaD D-lysine oxidase EC:1.4.3.3 ignore:BRENDA::P80340 dpkA 1-piperideine-2-carboxylate reductase EC:1.5.1.1 EC:1.5.1.21 amaA L-pipecolate oxidase EC:1.5.3.7 # Q4L235 is misannotated in BRENDA. # TIGR03443 hits both amaB and the ATP-hydrolyzing L-2-aminoadipate reductase. # P83402 and P84463 are short sequence fragments. # In MetaCyc, MONOMER-20455 is annotated as performing this reaction but was not given this EC number. # PP_5258 (Q88CC3) is in a newer version of metacyc. # SMc04385 (Q92L07) was identified using fitness data. amaB L-2-aminoadipate semialdehyde dehydrogenase (AmaB/Pcd) EC:1.2.1.31 ignore:BRENDA::Q4L235 ignore_hmm:TIGR03443 ignore:SwissProt::P83402 ignore:SwissProt::P84463 curated:metacyc::MONOMER-12387 uniprot:Q88CC3 uniprot:Q92L07 # In pathway V, the racemase alr forms D-lysine, which is oxidized to 6-amino-2-oxo-hexanoate, # spontaneously decarboxylates to 1-piperideine-2-carboxylate, # a reductase forms L-pipecolate, an oxidase forms 1-piperideine-6-carboxylate, # and a dehydrogenase forms L-2-aminoadipate. all: lysine-transport alr amaD dpkA amaA amaB L-2-aminoadipate-degradation lat L-lysine 6-aminotransferase EC:2.6.1.36 # In pathway VI, lysine 6-aminotransferase (lat) forms (S)-2-amino-6-oxohexanoate, # which spontaenously dehydrates to 1-piperideine 6-carboxylate, # and a dehydrogenase forms L-2-aminoadipate all: lysine-transport lat amaB L-2-aminoadipate-degradation lysDH L-lysine 6-dehydrogenase EC:1.4.1.18 # In pathway VIII, L-lysine 6-dehydrogenase (lysDH) # forms (S)-2-amino-6-oxohexanoate, which spontaenously dehydrates to # 1-piperideine 6-carboxylate, and a dehydrogenase forms # L-2-aminoadipate. all: lysine-transport lysDH amaB L-2-aminoadipate-degradation kamA L-lysine 2,3-aminomutase EC:5.4.3.2 kamD L-beta-lysine 5,6-aminomutase, alpha subunit curated:BRENDA::Q8RHX7 curated:SwissProt::E3PRJ5 kamE L-beta-lysine 5,6-aminomutase, beta subunit curated:BRENDA::Q8RHX8 curated:SwissProt::E3PRJ4 kdd 3,5-diaminohexanoate dehydrogenase EC:1.4.1.11 kce (S)-5-amino-3-oxohexanoate cleavage enzyme EC:2.3.1.247 kal 3-aminobutyryl-CoA deaminase EC:4.3.1.14 # D9TQ00 is probably misannotated in BRENDA # P52042 and metacyc::MONOMER-13470 and metacyc::MONOMER-11937 were given EC 1.3.8.1 # (which means electron transfer to etf, but no electron bifurcation expected), # but are probably electron bifurcating bcd butanoyl-CoA dehydrogenase (NAD+, ferredoxin), dehydrogenase subunit curated:BRENDA::D2RL84 curated:BRENDA::Q18AQ1 ignore:BRENDA::D9TQ00 curated:SwissProt::P52042 curated:metacyc::MONOMER-11937 curated:metacyc::MONOMER-13470 etfA butanoyl-CoA dehydrogenase (NAD+, ferredoxin), etfA subunit curated:BRENDA::D2RIQ3 curated:BRENDA::Q18AQ5 etfB butanoyl-CoA dehydrogenase (NAD+, ferredoxin), etfB subunit curated:BRENDA::D2RIQ2 curated:BRENDA::Q18AQ6 # cftAB are described in MetaCyc but are absent from the list of curated proteins # in this version of GapMind ctfA butanoyl-CoA:acetoacetate CoA-transferase, alpha subunit uniprot:P33752 ctfB butanoyl-CoA:acetoacetate CoA-transferase, beta subunit uniprot:P23673 # In the fermentative pathway, lysine 2,3-aminomutase (kamA) forms # L-beta-lysine, another aminomutase forms # (3S,5S)-3,5-diaminohexanoate, a dehydrogenase (deaminating) forms # (S)-5-amino-3-oxohexanoate, a cleavage enzyme (thiolase) uses # acetyl-CoA to form (S)-3-aminobutanoyl-CoA and acetoacetate, a # deaminase forms crotonyl-CoA, a dehydrogenase forms butanoyl-CoA, a # CoA-transferase converts the butanoyl-CoA and acetoacetate to # butanoate (a waste product) and acetoacetyl-CoA, and a # C-acetyltransferase (atoB) splits acetyl-CoA to two acetyl-CoA. all: lysine-transport kamA kamD kamE kdd kce kal bcd etfA etfB ctfA ctfB atoB
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:
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