Definition of L-isoleucine catabolism

As rules and steps, or see full text

Rules

Overview: Isoleucine degradation in GapMind is based on MetaCyc pathway L-isoleucine degradation I (link). The other pathways are fermentative and do not lead to carbon incorporation (link, link).

• all: isoleucine-transport, BKD, acdH, ech, ivdG, fadA and propionyl-CoA-degradation
  • Comment: A transaminase (which is not represented) converts isoleucine to (3S)-3-methyl-2-oxopentanoate, the decarboxylating dehydrogenase BKD forms (2S)-2-methylbutanoyl-CoA, dehydrogenase acdH forms (E)-2-methylcrotonyl-CoA, hydratase ech forms (2S,3S)-3-hydroxy-2-methylbutanoyl-CoA, dehydrogenase ivdG forms 2-methylacetoacetyl-CoA, and a thiolase forms propanioyl-CoA and acetyl-CoA. (The initial transaminase is not represented because amino-acid aminotransferases are often non-specific.)
• 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.
• isoleucine-transport:
  • livF, livG, livJ, livH and livM
  • or natA, natB, natC, natD and natE
  • or Bap2
  • or brnQ
  • or bcaP
  • Comment: Transporters were identified using query: transporter:isoleucine:L-isoleucine:ile and non-specific large neutral amino acid tranpsorters from mammals were ignored.

Steps

livF: L-isoleucine 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};
• UniProt sequence A0A165KC78: SubName: Full=ABC transporter ATP-binding protein {ECO:0000313|EMBL:KZT15317.1};
• UniProt sequence A0A159ZWL6: RecName: Full=High-affinity branched-chain amino acid transport ATP-binding protein {ECO:0000256|PIRNR:PIRNR039137};
• Comment: E. coli livFGHMJ or livFGHMK (livK and livJ are alternate SBPs). LivJFGHM from Streptococcus pneumoniae. BraCDEFG from Pseudomonas aeruginosa (braC is the SBP). BraDEFG/braC3 from R. leguminosarum; braC3 (RL3540; Q1MDE9) is a secondary SBP that transports leucine/isoleucine/valine/alanine (PMID:19597156); the proximal braC might also transport isoleucine, not sure if this is known, so exclude it (Q9L3M3); LivH/BraD = RL3750/Q1MCU0; LivM/BraE = RL3749/Q1MCU1; LivG/BraF = RL3748/Q1MCU2; LivF/BraG = RL3747/Q1MCU3; LivFGJHM from Acidovorax sp. GW101-3H11: LivF = Ac3H11_1692 (A0A165KC78), LivG = Ac3H11_1693 (A0A165KC86), LivJ = Ac3H11_2396 (A0A165KTD4; not near the other components, but cofit and has the phenotype on isoleucine), LivH = Ac3H11_1695 (A0A165KC95), LivM = Ac3H11_1694 (A0A165KER0); LivKHMGF from Pseudomonas fluorescens FW300-N2E2: LivF = Pf6N2E2_2926 = A0A159ZWL6, LivG = Pf6N2E2_2925 = A0A159ZWS6, LivK = Pf6N2E2_2921 = A0A160A0J6, LivH = Pf6N2E2_2923 = A0A0D9B2B6, LivM = Pf6N2E2_2924 = A0A159ZYE0
• Total: 6 characterized proteins

livG: L-isoleucine 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};
• UniProt sequence A0A165KC86: SubName: Full=ABC transporter ATP-binding protein {ECO:0000313|EMBL:KZT15318.1};
• UniProt sequence A0A159ZWS6: SubName: Full=High-affinity branched-chain amino acid ABC transporter ATP-binding protein LivG {ECO:0000313|EMBL:AMZ72285.1};
• Total: 6 characterized proteins

livJ: L-isoleucine 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 CH_107418: leucine-specific-binding protein LivK. Livk aka B3458, component of Leucine; leucine/isoleucine/valine porter. L-leucine/L-phenylalanine ABC transporter periplasmic binding protein (EC 7.4.2.2). L-leucine/L-phenylalanine ABC transporter periplasmic binding protein (EC 7.4.2.2)
• 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};
• Ignore hits to Q9L3M3 when looking for 'other' hits (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)
• UniProt sequence A0A165KTD4: SubName: Full=Branched chain amino acid ABC transporter substrate-binding protein {ECO:0000313|EMBL:KZT16064.1};
• UniProt sequence A0A160A0J6: SubName: Full=Leucine ABC transporter subunit substrate-binding protein LivK {ECO:0000313|EMBL:AMZ72282.1};
• Total: 7 characterized proteins

livH: L-isoleucine 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};
• UniProt sequence A0A165KC95: SubName: Full=ABC transporter permease {ECO:0000313|EMBL:KZT15319.1};
• UniProt sequence A0A0D9B2B6: SubName: Full=Branched-chain amino acid ABC transporter permease LivH {ECO:0000313|EMBL:AMZ72283.1}; SubName: Full=Branched-chain amino acid transporter permease subunit LivH {ECO:0000313|EMBL:KJH87425.1}; SubName: Full=L-leucine ABC transporter membrane protein /L-isoleucine ABC transporter membrane protein /L-valine ABC transporter membrane protein {ECO:0000313|EMBL:TCV66884.1};
• Total: 6 characterized proteins

livM: L-isoleucine 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};
• UniProt sequence A0A165KER0: SubName: Full=ABC transporter ATP-binding protein {ECO:0000313|EMBL:KZT15410.1};
• UniProt sequence A0A159ZYE0: SubName: Full=High-affinity branched-chain amino acid ABC transporter permease LivM {ECO:0000313|EMBL:AMZ72284.1};
• Comment: LivM from Streptococcus pneumoniae lacks an N-terminal domain of unknown function (DUF3382) that is found in E.coli and P. aeruginosa
• Total: 6 characterized proteins

natA: L-isoleucine 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; also a similar system in Anabaena (also known as N-I; TC 3.A.1.4.6) is thought to transport isoleucine (PMC4500139). A related system from Synechocystis (TC 3.A.1.4.2) transports a range of amino acids, but it is not clear that isoleucine is a substrate, so that system is marked ignore.
• Total: 1 characterized proteins

natB: L-isoleucine 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-isoleucine 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-isoleucine 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-isoleucine 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-isoleucine permease Bap2

• Curated sequence CH_091448: Leu/Val/Ile amino-acid permease. Leu/Val/Ile amino acid permease
• Curated sequence P38084: Leu/Val/Ile amino-acid permease; Branched-chain amino-acid permease 2
• Curated sequence Q2VQZ4: Arbuscular mycorrhizal fungal proline:H+ symporter, AAP1 (binds and probably transports nonpolar, hydrophobic amino acids)
• Total: 3 characterized proteins

brnQ: L-isoleucine: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
• Total: 3 characterized proteins

bcaP: L-isoleucine 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

• Curated proteins or TIGRFams with EC 4.2.1.79
• Total: 1 HMMs and 11 characterized proteins

acn: (2R,3S)-2-methylcitrate dehydratase

• Curated proteins or TIGRFams with EC 4.2.1.99
• Ignore hits to items matching 4.2.1.3 when looking for 'other' hits
• Comment: (2R,3S)-2-methylcitrate dehydratases are closely related to aconitate hydratases (EC 4.2.1.3), which are ignored.
• Total: 1 HMMs and 10 characterized proteins

prpB: 2-methylisocitrate lyase

• Curated proteins or TIGRFams with EC 4.1.3.30
• Ignore hits to items matching 4.1.3.1 when looking for 'other' hits
• Comment: Many 2-methylisocitrate lyases are closely related to isocitrate lyases (EC 4.1.3.1)
• Total: 1 HMMs and 26 characterized proteins

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

• Curated proteins or TIGRFams with EC 1.3.3.6
• Total: 27 characterized proteins

hpcD: 3-hydroxypropionyl-CoA dehydratase

• Curated proteins or TIGRFams with EC 4.2.1.116
• Total: 3 characterized proteins

dddA: 3-hydroxypropionate dehydrogenase

• Curated proteins or TIGRFams with EC 1.1.1.59
• Total: 2 characterized proteins

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

• Curated proteins or TIGRFams with EC 2.3.1.168
• Total: 11 characterized proteins

lpd: branched-chain alpha-ketoacid dehydrogenase, E3 component

• Curated proteins or TIGRFams with EC 1.8.1.4
• Total: 1 HMMs and 45 characterized proteins

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: (2S)-2-methylbutanoyl-CoA dehydrogenase

• Curated proteins or TIGRFams with EC 1.3.8.5
• Curated sequence PfGW456L13_2983: Short-chain acyl-CoA dehydrogenase (EC 1.3.8.1)
• Curated sequence 7025618: Branched-chain acyl-CoA dehydrogenase (EC 1.3.99.12)
• Curated sequence MONOMER-17424: short-chain acyl-CoA dehydrogenase monomer (EC 1.3.8.1)
• Ignore hits to GFF2392 when looking for 'other' hits (isobutyryl-CoA dehydrogenase (EC 1.3.8.1))
• Ignore hits to GFF2713 when looking for 'other' hits (isobutyryl-CoA dehydrogenase (EC 1.3.8.5))
• Ignore hits to PfGW456L13_2985 when looking for 'other' hits (isobutyryl-CoA dehydrogenase (EC 1.3.8.5))
• Ignore hits to AO353_25670 when looking for 'other' hits (isobutyryl-CoA dehydrogenase (EC 1.3.8.5))
• Ignore hits to P45857 when looking for 'other' hits (Acyl-CoA dehydrogenase; EC 1.3.99.-)
• Ignore hits to CH_091788 when looking for 'other' hits (acyl-CoA dehydrogenase)
• Comment: EC 1.3.8.5 includes (2S)-2-methylbutanoyl-CoA dehydrogenases and also isobutyryl-CoA dehydrogenases (involved in valine degradation) or sometimes 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 valine degradation and their activity on 2-methylbutanoyl-CoA uncertain, so they are marked ignore. PfGW456L13_2983 and Shewana3_2769 (VIMSS 7025618) and PP_2216 (MONOMER-17424) were annotated with other EC numbers (implying other acyl-CoA substrates) but are involved in isoleucine utilization, so are included. Various isobutyryl-CoA dehydrogenases are ignored (they may well act on 2-methylbutanoyl-CoA as well). P45857 (mmgC from B. subtilis) is part of an operon with methylcitrate cycle genes, and could be involved in isoleucine catabolism, but its biochemical activity is uncertain, so it is ignored, as is the nearly-identical CH_091788.
• Total: 14 characterized proteins

ech: 2-methyl-3-hydroxybutyryl-CoA hydro-lyase

• Curated proteins or TIGRFams with EC 4.2.1.17
• Curated sequence GFF2389: Enoyl-CoA hydratase [valine degradation] (EC 4.2.1.17)
• Ignore hits to items matching 4.2.1.150 when looking for 'other' hits
• 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))
• Ignore hits to PP_3358 when looking for 'other' hits (hydroxycinnamoyl-CoA hydratase-lyase (EC 4.2.1.17; EC 4.1.2.-))
• Comment: Psest_2437 (GFF2389) is the enoyl-CoA hydrotase for both isoleucine and valine degradation. A paper claiming that Q9SE41 (PMID:23809632) is ech relies on homology modeling, and it could well be a hydrolase instead; it is 69% identical to the hydrolase from Arabidopsis (Q9LKJ1). And MetaCyc linked Q51969 (MONOMER-11695) from P. putida to ech, but the sequence shown in the paper (PMID:12115060, Fig. 3) is different. And PP_3358 (hydroxycinnamoyl-CoA hydratase-lyase) was incorrectly given this EC number.
• Total: 1 HMMs and 35 characterized proteins

ivdG: 3-hydroxy-2-methylbutyryl-CoA dehydrogenase

• Curated proteins or TIGRFams with EC 1.1.1.178
• UniProt sequence Q8EGC1: SubName: Full=3-hydroxyacyl-CoA dehydrogenase IvdG {ECO:0000313|EMBL:AAN54738.1}; EC=1.1.1.35 {ECO:0000313|EMBL:AAN54738.1};
• Comment: SO1683 (Q8EGC1) was proposed to have this activity (PMC2612455; PMC3219624) and is important for isoleucine utilization.
• Total: 5 characterized proteins

fadA: 2-methylacetoacetyl-CoA thiolase

• Curated proteins or TIGRFams with EC 2.3.1.16
• Ignore hits to items matching 2.3.1.9 when looking for 'other' hits
• Comment: 2.3.1.9 is a similar reaction, acetoacetyl-CoA thiolase
• Total: 3 HMMs and 51 characterized proteins