L-isoleucine catabolism in Streptococcus massiliensis 4401825

Best path

livF, livG, livJ, livH, livM, ofo, acdH, ech, ivdG, fadA, pccA, pccB, epi, mcmA

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.

45 steps (19 with candidates)

Or see definitions of steps

Step	Description	Best candidate	2nd candidate
livF	L-isoleucine ABC transporter, ATPase component 1 (LivF/BraG)	BN415_RS07270	BN415_RS07275
livG	L-isoleucine ABC transporter, ATPase component 2 (LivG/BraF)	BN415_RS07275	BN415_RS07270
livJ	L-isoleucine ABC transporter, substrate-binding component (LivJ/LivK/BraC/BraC3)	BN415_RS07295	BN415_RS07290
livH	L-isoleucine ABC transporter, permease component 1 (LivH/BraD)	BN415_RS07285
livM	L-isoleucine ABC transporter, permease component 2 (LivM/BraE)	BN415_RS07280
ofo	branched-chain alpha-ketoacid:ferredoxin oxidoreductase, fused
acdH	(2S)-2-methylbutanoyl-CoA dehydrogenase
ech	2-methyl-3-hydroxybutyryl-CoA hydro-lyase	BN415_RS08100
ivdG	3-hydroxy-2-methylbutyryl-CoA dehydrogenase	BN415_RS08070	BN415_RS07795
fadA	2-methylacetoacetyl-CoA thiolase	BN415_RS07700
pccA	propionyl-CoA carboxylase, alpha subunit	BN415_RS08050
pccB	propionyl-CoA carboxylase, beta subunit
epi	methylmalonyl-CoA epimerase
mcmA	methylmalonyl-CoA mutase, fused catalytic and adenosylcobamide-binding components
Alternative steps:
acn	(2R,3S)-2-methylcitrate dehydratase
acnD	2-methylcitrate dehydratase (2-methyl-trans-aconitate forming)
Bap2	L-isoleucine permease Bap2
bcaP	L-isoleucine uptake transporter BcaP/CitA	BN415_RS04045
bkdA	branched-chain alpha-ketoacid dehydrogenase, E1 component alpha subunit	BN415_RS02005
bkdB	branched-chain alpha-ketoacid dehydrogenase, E1 component beta subunit	BN415_RS02000
bkdC	branched-chain alpha-ketoacid dehydrogenase, E2 component	BN415_RS01995
brnQ	L-isoleucine:cation symporter BrnQ/BraZ/BraB	BN415_RS02265
dddA	3-hydroxypropionate dehydrogenase
hpcD	3-hydroxypropionyl-CoA dehydratase
iolA	malonate semialdehyde dehydrogenase (CoA-acylating)
lpd	branched-chain alpha-ketoacid dehydrogenase, E3 component	BN415_RS01990	BN415_RS00555
mcm-large	methylmalonyl-CoA mutase, large (catalytic) subunit
mcm-small	methylmalonyl-CoA mutase, small (adenosylcobamide-binding) subunit
natA	L-isoleucine ABC transporter, ATPase component 1 (NatA)	BN415_RS07275	BN415_RS07270
natB	L-isoleucine ABC transporter, substrate-binding component NatB
natC	L-isoleucine ABC transporter, permease component 1 (NatC)
natD	L-isoleucine ABC transporter, permease component 2 (NatD)	BN415_RS07285
natE	L-isoleucine ABC transporter, ATPase component 2 (NatE)	BN415_RS07270	BN415_RS05735
ofoA	branched-chain alpha-ketoacid:ferredoxin oxidoreductase, alpha subunit OfoA
ofoB	branched-chain alpha-ketoacid:ferredoxin oxidoreductase, beta subunit OfoB
pccA1	propionyl-CoA carboxylase, biotin carboxyl carrier subunit	BN415_RS08050
pccA2	propionyl-CoA carboxylase, biotin carboxylase subunit
pco	propanyl-CoA oxidase
prpB	2-methylisocitrate lyase
prpC	2-methylcitrate synthase
prpD	2-methylcitrate dehydratase
prpF	methylaconitate isomerase
vorA	branched-chain alpha-ketoacid:ferredoxin oxidoreductase, alpha subunit VorA
vorB	branched-chain alpha-ketoacid:ferredoxin oxidoreductase, beta subunit VorB
vorC	branched-chain alpha-ketoacid:ferredoxin oxidoreductase, gamma subunit VorC

Confidence: high confidence medium confidence low confidence
transporter – transporters and PTS systems are shaded because predicting their specificity is particularly challenging.

This GapMind analysis is from Sep 24 2021. The underlying query database was built on Sep 17 2021.