Definition of L-valine catabolism
As rules and steps, or see full text
Rules
Overview: Valine degradation in GapMind is based on MetaCyc pathway L-valine degradation I (link). The other pathways do not produce any fixed carbon and are not included.
- all: valine-transport, BKD, acdH, ech, bch, mmsB, mmsA and propionyl-CoA-degradation
- Comment: An aminotransferase (not represented) forms 3-methyl-2-oxobutanoate, the decarboxylating alpha-ketoacid dehydrogenase (BKD) forms isobutanoyl-CoA, dehydrogenase acdH forms methylacrylyl-CoA (2-methylprop-2-enoyl-CoA), the hydratase ech forms (S)-3-hydroxy-isobutaonoyl-CoA, a hydrolase forms (S)-3-hydroxy-isobutanoate, a dehydrogenase forms (S)-methylmalonate semialdehyde (2-methyl-3-oxopropanoate), and a decarboxylating dehydrogenase forms propionyl-CoA.
- BKD:
- bkdA, bkdB, bkdC and lpd
- or vorA, vorB and vorC
- or ofoA and ofoB
- or ofo
- Comment: These decarboxylating dehydrogenases act on 4-methyl-2-oxopentanoate, 3-methyl-2-oxobutanoate (2-oxoisovalerate) and (S)-3-methyl-2-oxopentanoate and are known as the branched-chain alpha-ketoacid dehydrogenases. They can pass electrons to NAD (EC 1.2.1.25) or to ferredoxin (EC 1.2.7.7). The NAD-dependent enzyme is the sum of three activities: EC 1.2.4.4 (the 4-methyl-2-oxopentanoate dehydrogenase, with transfer to the lipopoyllysine residue of 2.3.1.168) which is itself heteromeric, with alpha and beta subunits; EC 2.3.1.168 (dihydrolipoyllysine-residue (3-methylbutanoyl)transferase); and EC 1.8.1.4 (dihydrolipoyl dehydrogenase, transferring electrons to NAD). The well-characterized ferredoxin-dependent enzymes have 3 subunits (vorABC) or 2 subunits (ofoAB). Genetic data identified a fused ferredoxin-dependent enzyme with just 1 subunit (ofo).
- propionyl-CoA-degradation:
- prpC, prpD, acn and prpB
- or prpC, acnD, prpF, acn and prpB
- or propionyl-CoA-carboxylase, epi and methylmalonyl-CoA-mutase
- or pco, hpcD, dddA and iolA
- Comment: In 2-methylcitrate cycle I, propionyl-CoA is combined with oxalacetate (by prpC) to give methylcitrate, dehydrated to cis-2-methylaconitate by prpD, hydrated to (2R,3S)-2-methylisocitrate, and a lyase produces pyruvate and succinate. (We consider succinate as a central intermediate, as most organisms can activate it to succinyl-CoA or can oxidize it to fumarate and convert that to oxaloacetate.) In 2-methylcitrate cycle II, a different dehydratase (acnD) and an isomerase (prpF) replace the dehydratase prpD; acnD dehydrates (2S,3S)-2-methylcitrate to 2-methyl-trans-aconitate, and prpF isomerizes it to cis-2-methylaconitate. In propanoyl CoA degradation I, propionyl-CoA carboxylase forms (S)-methylmalonyl-CoA, methylmalonyl-CoA epimerase forms (R)-methylmalonyl-CoA, and methylmalonyl-CoA mutase forms succinyl-CoA, which is a central metabolite. (Note that methylmalonyl-CoA mutase requires adenosylcobamide, a form of vitamin B12, for activity.) In propanoyl-CoA degradation II: propionyl-CoA is oxidized to acrylyl-CoA by pco, hydrated to 3-hydroxypropionyl-CoA, hydrolzed to 3-hydroxypropionate, oxidized to 3-oxopropionate (malonate semialdehyde), and oxidized to acetyl-CoA and CO2.
- methylmalonyl-CoA-mutase:
- mcmA
- or mcm-large and mcm-small
- Comment: methylmalonyl-CoA mutase has a catalytic domain and a B12-binding domain. These are usually found in the same protein, which we call mcmA. In Metallosphaera and Pyrococcus, the B12-binding domain is a separate subunit. In Propionibacterium and Methylorubrum, there is an additional subunit with a catalytic domain only; this may have a protective role (PMID:14734568) and is not described here. There's also a mcm-interacting GTPase (known as MeaB or YgfD) that loads B12 onto mcm and protects it from inactivation (see PMC4631608); this is not described here. Some fused mcm proteins include a MeaB domain as well (i.e., Q8F222, Q8Y2U5).
- propionyl-CoA-carboxylase:
- pccA and pccB
- or pccA1, pccA2 and pccB
- Comment: propionyl-CoA carboxylase is a heteromer, usually with alpha and beta subunits pccAB. Haloferax mediterranei has a third subunit as well (pccX), which is not described here. Acidianus brierleyi has a diverged pccA split into two pieces.
- valine-transport:
Steps
livF: L-valine ABC transporter, ATPase component 1 (LivF/BraG)
- Curated sequence CH_003736: high-affinity branched-chain amino acid ABC transporter, ATP-binding protein LivF. LivF aka B3454, component of Leucine; leucine/isoleucine/valine porter. branched chain amino acid/phenylalanine ABC transporter ATP binding subunit LivF (EC 7.4.2.2). branched chain amino acid/phenylalanine ABC transporter ATP binding subunit LivF (EC 7.4.2.2)
- Curated sequence P21630: High-affinity branched-chain amino acid transport ATP-binding protein BraG, component of Branched chain amino acid uptake transporter. Transports alanine
- Curated sequence Q8DQH7: ABC transporter ATP-binding protein-branched chain amino acid transport, component of The branched chain hydrophobic amino acid transporter, LivJFGHM
- UniProt sequence Q1MCU3: SubName: Full=ATP-binding component of a broad range amino acid ABC transporter {ECO:0000313|EMBL:CAK09237.1};
- Comment: ABC transporters with 5 components: E. coli livFGHMJ and related systems (but the alternate substrate-binding protein livK does not transport valine). Related systems include livJFGHM from Streptococcus pneumoniae, braCDEFG from Pseudomonas aeruginosa (braC is the SBP), and braCDEFG or braC3/braDEFG from R. leguminosarum. In R. leguminosarum, the proximal braC (Q9L3M3) transports leucine (PMC135202), and likely valine as well. braC3 (RL3540; Q1MDE9) is a secondary SBP that transports leucine/isoleucine/valine/alanine (PMID:19597156). LivH/BraD = RL3750/Q1MCU0; LivM/BraE = RL3749/Q1MCU1; LivG/BraF = RL3748/Q1MCU2; LivF/BraG = RL3747/Q1MCU3. (The related liv system from Acidovorax, Ac3H11_1692:1695 and Ac3H11_2396, has not been shown to transport valine.)
- Total: 4 characterized proteins
livG: L-valine ABC transporter, ATPase component 2 (LivG/BraF)
- Curated sequence P0A9S7: High-affinity branched-chain amino acid transport ATP-binding protein LivG aka B3455, component of Leucine; leucine/isoleucine/valine porter. branched chain amino acid/phenylalanine ABC transporter ATP binding subunit LivG (EC 7.4.2.2). branched chain amino acid/phenylalanine ABC transporter ATP binding subunit LivG (EC 7.4.2.2)
- Curated sequence P21629: High-affinity branched-chain amino acid transport ATP-binding protein BraF, component of Branched chain amino acid uptake transporter. Transports alanine
- Curated sequence Q8DQH8: ABC transporter ATP-binding protein-branched chain amino acid transport, component of The branched chain hydrophobic amino acid transporter, LivJFGHM
- UniProt sequence Q1MCU2: SubName: Full=ATP-binding component of a broad range amino acid ABC transporter {ECO:0000313|EMBL:CAK09238.1};
- Total: 4 characterized proteins
livJ: L-valine ABC transporter, substrate-binding component (LivJ/LivK/BraC/BraC3)
- Curated sequence P21175: Leucine-, isoleucine-, valine-, threonine-, and alanine-binding protein; LIVAT-BP; Leu/Ile/Val/Thr/Ala-binding protein. Leucine-, isoleucine-, valine-, threonine-, and alanine-binding protein, component of Branched chain amino acid uptake transporter. Transports alanine
- Curated sequence P0AD96: Leu/Ile/Val-binding protein LivJ aka B3460 aka LIV-BP, component of Leucine; leucine/isoleucine/valine porter. branched chain amino acid/phenylalanine ABC transporter periplasmic binding protein (EC 7.4.2.2). branched chain amino acid/phenylalanine ABC transporter periplasmic binding protein (EC 7.4.2.2)
- Curated sequence Q8DQI1: ABC transporter substrate-binding protein-branched chain amino acid transport, component of The branched chain hydrophobic amino acid transporter, LivJFGHM
- UniProt sequence Q1MDE9: SubName: Full=Solute-binding (Aliphatic amino acid) component of ABC transporter {ECO:0000313|EMBL:CAK09028.1};
- Curated sequence Q9L3M3: BraC, component of General L- (and D-)amino acid uptake porter (transports acidic, basic, polar, semipolar and hydrophobic amino acids). The amino and carboxyl groups do not need to be α since γ-aminobutyric acid (GABA) is a substrate. The system may function with additional binding proteins since L-alanine uptake is not dependent on BraC
- Total: 5 characterized proteins
livH: L-valine ABC transporter, permease component 1 (LivH/BraD)
- Curated sequence P21627: High-affinity branched-chain amino acid transport system permease protein BraD, component of Branched chain amino acid uptake transporter. Transports alanine
- Curated sequence Q8DQI0: ABC transporter membrane-spanning permease-branched chain amino acid transport, component of The branched chain hydrophobic amino acid transporter, LivJFGHM
- Curated sequence LIVH-MONOMER: branched chain amino acid/phenylalanine ABC transporter membrane subunit LivH (EC 7.4.2.2). high-affinity branched-chain amino acid ABC transporter, permease protein LivH. High-affinity branched-chain amino acid transport system permease protein LivH aka B3457, component of Leucine; leucine/isoleucine/valine porter. branched chain amino acid/phenylalanine ABC transporter membrane subunit LivH (EC 7.4.2.2)
- UniProt sequence Q1MCU0: SubName: Full=Transmembrane component of a broad range amino acid ABC transporter {ECO:0000313|EMBL:CAK09240.1};
- Total: 4 characterized proteins
livM: L-valine ABC transporter, permease component 2 (LivM/BraE)
- Curated sequence P22729: High-affinity branched-chain amino acid transport system permease protein LivM; LIV-I protein M. LivM aka B3456, component of Leucine; leucine/isoleucine/valine porter. branched chain amino acid/phenylalanine ABC transporter membrane subunit LivM (EC 7.4.2.2). branched chain amino acid/phenylalanine ABC transporter membrane subunit LivM (EC 7.4.2.2)
- Curated sequence P21628: High-affinity branched-chain amino acid transport system permease protein BraE, component of Branched chain amino acid uptake transporter. Transports alanine
- Curated sequence Q8DQH9: ABC transporter membrane-spanning permease-branched chain amino acid transport, component of The branched chain hydrophobic amino acid transporter, LivJFGHM
- UniProt sequence Q1MCU1: SubName: Full=Transmembrane component of a broad range amino acid ABC transporter {ECO:0000313|EMBL:CAK09239.1};
- Comment: LivM from Streptococcus pneumoniae lacks an N-terminal domain of unknown function (DUF3382) that is found in E.coli and P. aeruginosa
- Total: 4 characterized proteins
natA: L-valine ABC transporter, ATPase component 1 (NatA)
- Ignore hits to Q55164 when looking for 'other' hits (NatA aka BRAF aka SLR0467, component of Leucine/proline/alanine/serine/glycine (and possibly histidine) porter, NatABCDE)
- Curated sequence Q7A2H0: NatA, component of The neutral amino acid permease, N-1 (transports pro, phe, leu, gly, ala, ser, gln and his, but gln and his are not transported via NatB)
- Comment: Synechocystis sp. NatABCDE TC 3.A.1.4.2) and a similar system from Anabaena (also known as N-I; TC 3.A.1.4.6) are reported to transport many amino acids. There isn't any data for valine transport in Synechocystis, but N-I from Anabaena is thought to contribute to the reuptake of valine that leaks from the cell (PMC4500139).
- Total: 1 characterized proteins
natB: L-valine ABC transporter, substrate-binding component NatB
- Ignore hits to Q55387 when looking for 'other' hits (NatB aka SLR0559, component of Leucine/proline/alanine/serine/glycine (and possibly histidine) porter, NatABCDE)
- Curated sequence Q8YVY4: NatB, component of The neutral amino acid permease, N-1 (transports pro, phe, leu, gly, ala, ser, gln and his, but gln and his are not transported via NatB)
- Total: 1 characterized proteins
natC: L-valine ABC transporter, permease component 1 (NatC)
- Ignore hits to P74455 when looking for 'other' hits (NatC aka SLL0146, component of Leucine/proline/alanine/serine/glycine (and possibly histidine) porter, NatABCDE)
- Curated sequence Q8YY08: NatC, component of The neutral amino acid permease, N-1 (transports pro, phe, leu, gly, ala, ser, gln and his, but gln and his are not transported via NatB)
- Total: 1 characterized proteins
natD: L-valine ABC transporter, permease component 2 (NatD)
- Ignore hits to P74318 when looking for 'other' hits (NatD aka LivH aka SLR0949, component of Leucine/proline/alanine/serine/glycine (and possibly histidine) porter, NatABCDE)
- Curated sequence Q8YXD0: NatD, component of The neutral amino acid permease, N-1 (transports pro, phe, leu, gly, ala, ser, gln and his, but gln and his are not transported via NatB)
- Total: 1 characterized proteins
natE: L-valine ABC transporter, ATPase component 2 (NatE)
- Ignore hits to P73650 when looking for 'other' hits (NatE aka LivF aka SLR1881, component of Leucine/proline/alanine/serine/glycine (and possibly histidine) porter, NatABCDE)
- Curated sequence Q8YT15: NatE, component of The neutral amino acid permease, N-1 (transports pro, phe, leu, gly, ala, ser, gln and his, but gln and his are not transported via NatB)
- Total: 1 characterized proteins
Bap2: L-valine permease Bap2
- Curated sequence CH_091448: Leu/Val/Ile amino-acid permease. Leu/Val/Ile amino acid permease
- Curated sequence CH_091631: valine/tyrosine/tryptophan amino-acid permease. Valine/tyrosine/tryptophan amino-acid permease 1; Tyrosine and tryptophan amino acid transporter 1. Val/Tyr/Trp permease
- Curated sequence P38084: Leu/Val/Ile amino-acid permease; Branched-chain amino-acid permease 2
- Curated sequence P41815: Valine amino-acid permease; Branched-chain amino-acid permease 3. Valine amino-acid permease (Branched-chain amino-acid permease 3)
- Curated sequence Q2VQZ4: Arbuscular mycorrhizal fungal proline:H+ symporter, AAP1 (binds and probably transports nonpolar, hydrophobic amino acids)
- Total: 5 characterized proteins
brnQ: L-valine:cation symporter BrnQ/BraZ/BraB
- Curated sequence P0AD99: Branched chain amino acid transporter 2 of 439 aas and 12 TMSs, BrnQ. branched chain amino acid transporter BrnQ. branched chain amino acid transporter BrnQ
- Curated sequence P25185: Ile/Val:H+ symporter
- Curated sequence P19072: Branched chain amino acid: Na+ symporter
- Comment: E. coli BrnQ is reported to use Na+, while P. aeruginosa BraZ is reported to use H+
- Total: 3 characterized proteins
phtJ: L-valine uptake permease PhtJ
- Curated sequence Q5ZUB4: The valine uptake permease, PhtJ (required for maximal growth in macrophages and Acanthamoeba castellanii)
- Total: 1 characterized proteins
bcaP: L-valine uptake transporter BcaP/CitA
- Curated sequence S6EX81: Branched chain amino acid (Leucine/isoleucine/valine) uptake transporter of 469 aas and 12 TMSs, BcaP or CitA
- Total: 1 characterized proteins
pccA: propionyl-CoA carboxylase, alpha subunit
- Curated sequence P05165: propionyl-CoA carboxylase (subunit 1/2) (EC 6.4.1.3). Propionyl-CoA carboxylase alpha chain, mitochondrial; PCCase subunit alpha; Propanoyl-CoA:carbon dioxide ligase subunit alpha; EC 6.4.1.3. propionyl-CoA carboxylase α chain, mitochondrial (EC 6.4.1.3)
- Curated sequence Q19842: propionyl-CoA carboxylase (subunit 2/2) (EC 6.4.1.3). Propionyl-CoA carboxylase alpha chain, mitochondrial; PCCase subunit alpha; Propanoyl-CoA:carbon dioxide ligase subunit alpha; EC 6.4.1.3
- Curated sequence I3R7G3: Propionyl-CoA carboxylase, biotin carboxylase and biotin-carboxyl carrier subunit; PCC; EC 6.4.1.3; EC 6.3.4.14. propionyl-CoA carboxylase (subunit 3/3) (EC 6.4.1.3)
- Curated sequence P0DTA4: Propionyl-CoA carboxylase alpha chain, mitochondrial; PCCase subunit alpha; Propanoyl-CoA:carbon dioxide ligase subunit alpha; EC 6.4.1.3
- Curated sequence Q5LUF3: Propionyl-CoA carboxylase alpha chain; EC 6.4.1.3. propionyl-CoA carboxylase (EC 6.4.1.3)
- Curated sequence Q91ZA3: Propionyl-CoA carboxylase alpha chain, mitochondrial; PCCase subunit alpha; Propanoyl-CoA:carbon dioxide ligase subunit alpha; EC 6.4.1.3
- Curated sequence MONOMER-13589: propionyl-CoA carboxylase α subunit (EC 6.4.1.3)
- Curated sequence MONOMER-8606: propionyl-CoA carboxylase α subunit (EC 6.4.1.3)
- Curated sequence 3607308: Propionyl-CoA carboxylase biotin-containing subunit (EC 6.4.1.3)
- Curated sequence Dsui_0516: Propionyl-CoA carboxylase biotin-containing subunit (EC 6.4.1.3)
- Ignore hits to items matching 6.4.1.3 when looking for 'other' hits
- Total: 10 characterized proteins
pccB: propionyl-CoA carboxylase, beta subunit
- Curated sequence P05166: propionyl-CoA carboxylase (subunit 2/2) (EC 6.4.1.3). Propionyl-CoA carboxylase beta chain, mitochondrial; PCCase subunit beta; Propanoyl-CoA:carbon dioxide ligase subunit beta; EC 6.4.1.3. propionyl-CoA carboxylase β chain, mitochondrial (EC 6.4.1.3)
- Curated sequence Q20676: propionyl-CoA carboxylase (subunit 1/2) (EC 6.4.1.3)
- Curated sequence Q9X4K7: propionyl-CoA carboxylase (EC 6.4.1.3)
- Curated sequence I3R7F1: Propionyl-CoA carboxylase, carboxyltransferase subunit; PCC; EC 6.4.1.3. propionyl-CoA carboxylase (subunit 2/3) (EC 6.4.1.3)
- Curated sequence P53003: Propionyl-CoA carboxylase beta chain; PCCase; Propanoyl-CoA:carbon dioxide ligase; EC 6.4.1.3
- Curated sequence P79384: Propionyl-CoA carboxylase beta chain, mitochondrial; PCCase subunit beta; Propanoyl-CoA:carbon dioxide ligase subunit beta; EC 6.4.1.3
- Curated sequence Q168G2: Propionyl-CoA carboxylase beta chain; EC 6.4.1.3
- Curated sequence Q3J4E3: Propionyl-CoA carboxylase beta chain; PCCase; Propanoyl-CoA:carbon dioxide ligase; EC 6.4.1.3. propionyl-CoA carboxylase β subunit (EC 6.4.1.3)
- Curated sequence Q99MN9: Propionyl-CoA carboxylase beta chain, mitochondrial; PCCase subunit beta; Propanoyl-CoA:carbon dioxide ligase subunit beta; EC 6.4.1.3. propionyl-CoA carboxylase (EC 6.4.1.3)
- Curated sequence MONOMER-13598: acyl CoA carboxylase carboxyltransferase subunit (EC 2.1.3.15; EC 6.4.1.3; EC 6.3.4.14). acetyl-CoA carboxylase (subunit 1/3) (EC 6.4.1.2); propionyl-CoA carboxylase (subunit 2/3) (EC 6.4.1.3)
- Curated sequence MONOMER-16260: propionyl-CoA carboxylase (EC 6.4.1.3)
- Curated sequence MONOMER-17283: propionyl-CoA carboxylase α subunit (EC 6.4.1.3)
- Curated sequence MONOMER-17284: propionyl-CoA carboxylase β subunit (EC 6.4.1.3)
- Curated sequence MONOMER-8607: propionyl-CoA carboxylase β subunit (EC 6.4.1.3)
- Curated sequence 3607303: Propionyl-CoA carboxylase carboxyl transferase subunit (EC 6.4.1.3)
- Curated sequence Dsui_0517: Propionyl-CoA carboxylase carboxyl transferase subunit (EC 6.4.1.3)
- Ignore hits to items matching 6.4.1.3 when looking for 'other' hits
- Total: 16 characterized proteins
pccA1: propionyl-CoA carboxylase, biotin carboxyl carrier subunit
- Curated sequence MONOMER-13597: acyl CoA carboxylase biotin carboxylase subunit (EC 2.1.3.15; EC 6.4.1.3; EC 6.3.4.14). biotin carboxylase (EC 6.3.4.14); acetyl-CoA carboxylase (subunit 2/3) (EC 6.4.1.2); propionyl-CoA carboxylase (subunit 1/3) (EC 6.4.1.3)
- Ignore hits to items matching 6.4.1.3 when looking for 'other' hits
- Total: 1 characterized proteins
pccA2: propionyl-CoA carboxylase, biotin carboxylase subunit
- Curated sequence MONOMER-13596: acyl CoA carboxylase biotin carboxyl carrier protein subunit (EC 2.1.3.15; EC 6.4.1.3; EC 6.3.4.14). acetyl-CoA carboxylase (subunit 3/3) (EC 6.4.1.2); propionyl-CoA carboxylase (subunit 3/3) (EC 6.4.1.3)
- Ignore hits to items matching 6.4.1.3 when looking for 'other' hits
- Total: 1 characterized proteins
mcmA: methylmalonyl-CoA mutase, fused catalytic and adenosylcobamide-binding components
- Curated sequence O86028: Methylmalonyl-CoA mutase; MCM; EC 5.4.99.2
- Curated sequence P22033: methylmalonyl-CoA mutase (EC 5.4.99.2). Methylmalonyl-CoA mutase, mitochondrial; MCM; Methylmalonyl-CoA isomerase; EC 5.4.99.2. Methylmalonyl-CoA mutase, mitochondrial (EC 5.4.99.2)
- Curated sequence Q23381: methylmalonyl-CoA mutase (EC 5.4.99.2)
- Curated sequence Q84FZ1: methylmalonyl-CoA mutase (EC 5.4.99.2)
- Curated sequence Q8MI68: methylmalonyl-CoA mutase (EC 5.4.99.2)
- Curated sequence P27253: Methylmalonyl-CoA mutase; MCM; EC 5.4.99.2. methylmalonyl-CoA mutase (EC 5.4.99.2). methylmalonyl-CoA mutase (EC 5.4.99.2)
- Curated sequence Q3J4D7: Methylmalonyl-CoA mutase; MCM; EC 5.4.99.2. methylmalonyl-CoA mutase (EC 5.4.99.2)
- Curated sequence MONOMER-18293: methylmalonyl-CoA mutase subunit (EC 5.4.99.2)
- Curated sequence Dsui_0519: Methylmalonyl-CoA mutase (EC 5.4.99.2)
- Curated sequence Q8F222: methylmalonyl-CoA mutase (EC 5.4.99.2)
- Curated sequence Q8Y2U5: methylmalonyl-CoA mutase (EC 5.4.99.2)
- Ignore hits to items matching 5.4.99.2 when looking for 'other' hits
- Total: 11 characterized proteins
mcm-large: methylmalonyl-CoA mutase, large (catalytic) subunit
- Curated sequence A4YEG1: methylmalonyl-CoA mutase (subunit 2/2) (EC 5.4.99.2)
- Curated sequence O74009: methylmalonyl-CoA mutase (subunit 2/2) (EC 5.4.99.2)
- Curated sequence P11653: methylmalonyl-CoA mutase (EC 5.4.99.2). Methylmalonyl-CoA mutase large subunit; MCM-alpha; EC 5.4.99.2. methylmalonyl-CoA mutase large subunit (EC 5.4.99.2)
- Ignore hits to items matching 5.4.99.2 when looking for 'other' hits
- Total: 3 characterized proteins
mcm-small: methylmalonyl-CoA mutase, small (adenosylcobamide-binding) subunit
- Curated sequence A4YIE3: methylmalonyl-CoA mutase (subunit 1/2) (EC 5.4.99.2)
- Curated sequence O58013: methylmalonyl-CoA mutase (subunit 1/2) (EC 5.4.99.2)
- Ignore hits to items matching 5.4.99.2 when looking for 'other' hits
- Total: 2 characterized proteins
prpC: 2-methylcitrate synthase
- Curated proteins or TIGRFams with EC 2.3.3.5
- Curated sequence P45858: citrate synthase (unknown stereospecificity) (EC 2.3.3.16). Citrate/2-methylcitrate synthase; 2-methylcitrate synthase; 2-MCS; MCS; Citrate synthase; EC 2.3.3.-; EC 2.3.3.16
- Comment: P45858 is annotated by SwissProt as 2-methylcitrate synthase, but without this EC number
- Total: 19 characterized proteins
prpD: 2-methylcitrate dehydratase
acn: (2R,3S)-2-methylcitrate dehydratase
prpB: 2-methylisocitrate lyase
acnD: 2-methylcitrate dehydratase (2-methyl-trans-aconitate forming)
- Curated proteins or TIGRFams with EC 4.2.1.117
- Ignore hits to Q937N8 when looking for 'other' hits (Aconitate hydratase A; Aconitase; (2R,3S)-2-methylisocitrate dehydratase; (2S,3R)-3-hydroxybutane-1,2,3-tricarboxylate dehydratase; Iron-responsive protein-like; IRP-like; Probable 2-methyl-cis-aconitate hydratase; RNA-binding protein; EC 4.2.1.3; EC 4.2.1.99)
- Comment: acnM from Ralstonia eutropha (Q937N8) is proposed to have this activity as well (PMID:11495997), but is annotated in SwissProt as aconitase or (2R,3S)-2-methylisocitrate dehydratase instead
- Total: 1 characterized proteins
prpF: methylaconitate isomerase
- Curated proteins or TIGRFams with EC 5.3.3.7
- Curated sequence Q937N7: 2-methyl-aconitate isomerase; Cis-trans isomerase; EC 5.3.3.-
- Ignore hits to A0A0A1H8I4 when looking for 'other' hits (Aconitate isomerase; AI; EC 5.3.3.7. aconitate DELTA-isomerase (EC 5.3.3.7))
- Comment: SwissProt annotates Q937N7 with this activity, but with a vague EC number. The periplasmic substrate-binding protein A0A0A1H8I4 has aconitate isomerase activity but has a high Km (PMID:26293748), and its periplasmic location would prevent it from participating in the methylcitrate cycle, so it is ignored.
- Total: 3 characterized proteins
epi: methylmalonyl-CoA epimerase
- Curated proteins or TIGRFams with EC 5.1.99.1
- Ignore hits to 3607309 when looking for 'other' hits (Methylmalonyl-CoA epimerase (EC 5.1.99.1))
- Comment: In the fitness browser reannotations, Dshi_0724 from Dinoroseobacter shibae (Dino:3607309) was annotated as the epimerase because it was annotated as such by SEED and it has a specific phenotype on propionate, which seemed to confirm its annotation. But Dshi_0724 belongs to the uncharacterized family DUF4174 / PF13778 and has a signal peptide. Also, D. shibae contains another, apparently essential, epi (Dshi_2630).
- Total: 1 HMMs and 9 characterized proteins
pco: propanyl-CoA oxidase
hpcD: 3-hydroxypropionyl-CoA dehydratase
dddA: 3-hydroxypropionate dehydrogenase
iolA: malonate semialdehyde dehydrogenase (CoA-acylating)
- Curated proteins or TIGRFams with EC 1.2.1.18
- Ignore hits to items matching 1.2.1.27 when looking for 'other' hits
- Ignore hits to Q9I702 when looking for 'other' hits (Putative 3-oxopropanoate dehydrogenase; EC 1.2.1.-)
- Comment: Ignore similarity to methylmalonate semialdehyde dehydrogenase (EC 1.2.1.27), which often has this activity as well
- Total: 11 characterized proteins
bkdA: branched-chain alpha-ketoacid dehydrogenase, E1 component alpha subunit
- Curated sequence P12694: 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial; Branched-chain alpha-keto acid dehydrogenase E1 component alpha chain; BCKDE1A; BCKDH E1-alpha; EC 1.2.4.4. branched-chain α-keto acid dehydrogenase E1 component α subunit (EC 1.2.4.4)
- Curated sequence Q72GU1: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) (EC 1.2.4.4)
- Curated sequence CH_121278: 2-oxoisovalerate dehydrogenase subunit alpha; EC 1.2.4.4
- Curated sequence O45924: 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial; Branched-chain alpha-keto acid dehydrogenase E1 component alpha chain; EC 1.2.4.4
- Curated sequence P11178: 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial; Branched-chain alpha-keto acid dehydrogenase E1 component alpha chain; BCKDE1A; BCKDH E1-alpha; EC 1.2.4.4
- Curated sequence P9WIS3: 3-methyl-2-oxobutanoate dehydrogenase subunit alpha; Branched-chain alpha-ketoacid dehydrogenase E1 component subunit alpha; BCKADH E1-alpha; EC 1.2.4.4
- Curated sequence Q5SLR4: 2-oxoisovalerate dehydrogenase subunit alpha; Branched-chain alpha-keto acid dehydrogenase E1 component alpha chain; BCKDH E1-alpha; EC 1.2.4.4
- Curated sequence Q84JL2: 2-oxoisovalerate dehydrogenase subunit alpha 2, mitochondrial; Branched-chain alpha-keto acid dehydrogenase E1 component alpha chain; BCKDE1A; BCKDH E1-alpha; EC 1.2.4.4
- Curated sequence Q9LPL5: 2-oxoisovalerate dehydrogenase subunit alpha 1, mitochondrial; Branched-chain alpha-keto acid dehydrogenase E1 component alpha chain; BCKDE1A; BCKDH E1-alpha; EC 1.2.4.4
- Curated sequence SMc03201: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) (EC 1.2.4.4)
- Curated sequence PfGW456L13_3540: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) (EC 1.2.4.4)
- Curated sequence AO353_26635: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) (EC 1.2.4.4)
- Curated sequence AO356_22990: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) (EC 1.2.4.4)
- Curated sequence Pf6N2E2_481: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) (EC 1.2.4.4)
- Curated sequence MONOMER-11683: 2-keto-isovalerate dehydrogenase component α subunit (EC 1.2.4.4)
- Total: 15 characterized proteins
bkdB: branched-chain alpha-ketoacid dehydrogenase, E1 component beta subunit
- Curated sequence CH_121283: 2-oxoisovalerate dehydrogenase subunit beta; EC 1.2.4.4
- Curated sequence P21953: 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial; Branched-chain alpha-keto acid dehydrogenase E1 component beta chain; BCKDE1B; BCKDH E1-beta; EC 1.2.4.4. branched-chain α-keto acid dehydrogenase E1 component β subunit (EC 1.2.4.4)
- Curated sequence P9WIS1: 3-methyl-2-oxobutanoate dehydrogenase subunit beta; Branched-chain alpha-ketoacid dehydrogenase E1 component subunit beta; BCKADH E1-beta; EC 1.2.4.4
- Curated sequence Q5SLR3: 2-oxoisovalerate dehydrogenase subunit beta; Branched-chain alpha-keto acid dehydrogenase E1 component beta chain; BCKDH E1-beta; EC 1.2.4.4
- Curated sequence Q9LDY2: 2-oxoisovalerate dehydrogenase subunit beta 2, mitochondrial; Branched-chain alpha-keto acid dehydrogenase E1 component beta chain; BCKDE1B; BCKDH E1-beta; Protein DARK INDUCIBLE 4; EC 1.2.4.4
- Curated sequence MONOMER-11684: 2-keto-isovalerate dehydrogenase component β subunit (EC 1.2.4.4)
- Curated sequence SMc03202: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) (EC 1.2.4.4)
- Curated sequence GFF3430: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) (EC 1.2.4.4)
- Curated sequence PfGW456L13_3541: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) (EC 1.2.4.4)
- Curated sequence AO356_22985: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) (EC 1.2.4.4)
- Curated sequence Pf6N2E2_480: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) (EC 1.2.4.4)
- Curated sequence Q9HIA4: branched-chain-2-oxoacid decarboxylase (subunit 2/2) (EC 4.1.1.72)
- Total: 12 characterized proteins
bkdC: branched-chain alpha-ketoacid dehydrogenase, E2 component
lpd: branched-chain alpha-ketoacid dehydrogenase, E3 component
vorA: branched-chain alpha-ketoacid:ferredoxin oxidoreductase, alpha subunit VorA
- Curated sequence P80907: Ketoisovalerate oxidoreductase subunit VorA; VOR; 2-oxoisovalerate oxidoreductase alpha chain; 2-oxoisovalerate-ferredoxin oxidoreductase subunit alpha; EC 1.-.-.-
- Ignore hits to items matching 1.2.7.7 when looking for 'other' hits
- Total: 1 characterized proteins
vorB: branched-chain alpha-ketoacid:ferredoxin oxidoreductase, beta subunit VorB
- Curated sequence P80908: Ketoisovalerate oxidoreductase subunit VorB; VOR; 2-oxoisovalerate ferredoxin reductase subunit beta; 2-oxoisovalerate oxidoreductase beta chain; EC 1.2.7.7
- Ignore hits to items matching 1.2.7.7 when looking for 'other' hits
- Total: 1 characterized proteins
vorC: branched-chain alpha-ketoacid:ferredoxin oxidoreductase, gamma subunit VorC
- Curated sequence P80909: Ketoisovalerate oxidoreductase subunit VorC; VOR; 2-oxoisovalerate ferredoxin reductase subunit gamma; 2-oxoisovalerate oxidoreductase gamma chain; EC 1.2.7.7
- Ignore hits to items matching 1.2.7.7 when looking for 'other' hits
- Total: 1 characterized proteins
ofoA: branched-chain alpha-ketoacid:ferredoxin oxidoreductase, alpha subunit OfoA
- Curated sequence P72578: 2-oxoacid:ferredoxin oxidoreductase subunit alpha; OFOR; EC 1.2.7.11. 2-oxoacid oxidoreductase (ferredoxin) (subunit 2/2) (EC 1.2.7.11). 2-oxoacid:ferredoxin oxidoreductase α subunit (EC 1.2.7.11; EC 1.2.7.1; EC 1.2.7.3; EC 1.2.7.7)
- Ignore hits to items matching 1.2.7.7 when looking for 'other' hits
- Ignore hits to items matching 1.2.7.11 when looking for 'other' hits
- Comment: ofoAB is similar to low-specificity 2-oxoacid oxidoreductases (EC 1.2.7.11); it is generally not certain if these act on 4-methyl-2-oxopentanoate or not, but they probably do.
- Total: 1 characterized proteins
ofoB: branched-chain alpha-ketoacid:ferredoxin oxidoreductase, beta subunit OfoB
- Curated sequence P72579: 2-oxoacid:ferredoxin oxidoreductase subunit beta; OFOR; EC 1.2.7.11. 2-oxoacid oxidoreductase (ferredoxin) (subunit 1/2) (EC 1.2.7.11). 2-oxoacid:ferredoxin oxidoreductase β subunit (EC 1.2.7.11; EC 1.2.7.1; EC 1.2.7.3; EC 1.2.7.7)
- Ignore hits to items matching 1.2.7.7 when looking for 'other' hits
- Ignore hits to items matching 1.2.7.11 when looking for 'other' hits
- Total: 1 characterized proteins
ofo: branched-chain alpha-ketoacid:ferredoxin oxidoreductase, fused
- Curated sequence RR42_RS19540: 3-methyl-2-oxobutanoate:ferredoxin oxidoreductase (EC 1.2.7.7)
- Curated sequence GFF3452: branched-chain ketoacid ferredoxin reductase (EC 1.2.7.7) active on 4-methyl-2-oxopentanoate, (S)-3-methyl-2-oxopentanoate, or 3-methyl-2-oxobutanoate
- Ignore hits to items matching 1.2.7.7 when looking for 'other' hits
- Ignore hits to items matching 1.2.7.11 when looking for 'other' hits
- Total: 2 characterized proteins
acdH: isobutyryl-CoA dehydrogenase
- Curated proteins or TIGRFams with EC 1.3.8.5
- Ignore hits to 200844 when looking for 'other' hits (2-methylbutanoyl-CoA dehydrogenase (EC 1.3.8.5))
- Ignore hits to GFF2715 when looking for 'other' hits (2-methylbutanoyl-CoA dehydrogenase (EC 1.3.8.5))
- Ignore hits to Ac3H11_2996 when looking for 'other' hits (2-methyl-branched-chain-enoyl-CoA reductase (EC 1.3.8.5))
- Ignore hits to GFF2397 when looking for 'other' hits (2-methylbutanoyl-CoA dehydrogenase (EC 1.3.8.5))
- Ignore hits to Pf1N1B4_4787 when looking for 'other' hits (2-methylbutanoyl-CoA dehydrogenase (EC 1.3.8.5))
- Ignore hits to AO356_26355 when looking for 'other' hits (2-methylbutanoyl-CoA dehydrogenase (EC 1.3.8.5))
- Ignore hits to Pf6N2E2_1146 when looking for 'other' hits (2-methylbutanoyl-CoA dehydrogenase (EC 1.3.8.5))
- Ignore hits to PfGW456L13_2983 when looking for 'other' hits (Short-chain acyl-CoA dehydrogenase (EC 1.3.8.1))
- Curated sequence GFF2392: isobutyryl-CoA dehydrogenase (EC 1.3.8.1)
- Ignore hits to MONOMER-17424 when looking for 'other' hits (short-chain acyl-CoA dehydrogenase monomer (EC 1.3.8.1))
- Comment: EC 1.3.8.5 includes isobutyryl-CoA dehydrogenases and sometimes (2S)-2-methylbutanoyl-CoA dehydrogenases (involved in isoleucine degradation, usually given EC 1.3.8.5 as well) or 3-methylbutanoyl-CoA dehydrogenases (involved in leucine degradation, usually given EC 1.3.8.4). Some enzymes act on all three methylacyl-CoA substrates. Other genes are required only for isoleucine degradation and their activity on isobutyryl-CoA is uncertain, so they are marked ignore. Also add Psest_2440 (GFF2392), given a different EC number, and ignore PfGW456L13_2983 (given a different EC but involved in isoleucine degradation) and PP_2216 (MONOMER-17424), also involved in isoleucine degradation.
- Total: 8 characterized proteins
ech: (S)-3-hydroxybutanoyl-CoA hydro-lyase
- Curated proteins or TIGRFams with EC 4.2.1.150
- Ignore hits to Q97MS7 when looking for 'other' hits (short-chain-enoyl-CoA hydratase (EC 4.2.1.150))
- Curated sequence BPHYT_RS17335: trans-2,3-dehydroadipyl-CoA hydratase (EC 4.2.1.17)
- Curated sequence GFF2389: Enoyl-CoA hydratase [valine degradation] (EC 4.2.1.17)
- Ignore hits to items matching 4.2.1.17 when looking for 'other' hits
- Comment: Psest_2437 (GFF2389) is the enoyl-CoA hydrotase for both isoleucine and valine degradation, which implies that (S)-3-hydroxybutanoyl-CoA is a substrate. Q97MS7 is misannotated in BRENDA. BPHYT_RS17335 was misannotated as paaF; it is very similar to the ech H16_A3307, which is a different explanation for its role in phenylacetate utilization. Short-chain enoyl-CoA hydratases are sometimes given EC 4.2.1.17 instead, so those are ignored.
- Total: 8 characterized proteins
bch: 3-hydroxyisobutyryl-CoA hydrolase
- Curated proteins or TIGRFams with EC 3.1.2.4
- Ignore hits to Q9SE41 when looking for 'other' hits (enoyl-CoA hydratase (EC 4.2.1.17))
- Ignore hits to MONOMER-11695 when looking for 'other' hits (enoyl-CoA hydratase subunit (EC 4.2.1.17))
- Total: 13 characterized proteins
mmsB: 3-hydroxyisobutyrate dehydrogenase
mmsA: methylmalonate-semialdehyde dehydrogenase
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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, 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