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:
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