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Catalytic Site Atlas Version 2.2.12
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CSA entry for 1mfp
Original Entry
Title:
Oxidoreductase
Compound:
Enoyl-[acyl-carrier-protein] reductase [nadh]
Mutant:
No
UniProt/Swiss-Prot:
P29132-FABI_ECOLI
EC Class:
1.3.1.9
Other CSA Entries:
Overview of all sites for 1mfp
Homologues of 1mfp
Entries for UniProt/Swiss-Prot: P29132
Entries for EC: 1.3.1.9
Other Databases:
PDB entry: 1mfp
PDBsum entry: 1mfp
UniProt/Swiss-Prot: P29132
IntEnz entry: 1.3.1.9
Literature Report:
Introduction:
FabI catalyses the final step of fatty acid biosynthesis. Therefore it is a potential target for antibacterial agent development. It catalyses the NAD(P)H-dependent reduction of enoyl acyl carrier protein. EACPR's show homology, and similarity to hydroxysteroid dehydrogenase, and also beta-keto reductase, suggesting divergent evolution has played a role in the development of the pathway of lipid biosynthesis.
Mechanism:
The catalytic mechanism involves C3 of the substrate being subject to hydride attack by NADH, a bound cofactor. Formation of an enolate intermediate follows, which accepts a proton from Tyr 156. A role in transition state stabilisation through hydrogen bonding has also been suggested for Tyr 156. The enol product would then tautomerise to give the reduced acyl product. Tyr 156 therefore acts as the base that donates the proton to the enolate anion, and Lys 163 acts to stabilise the negatively charged transition state.
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Found by:
Literature reference 
PsiBLAST alignment on 1qsg

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
301 0Sidechain
Electron donor/acceptorSubstrate
Participates in hydride transfer.
Evidence from paper Evidence concerns Evidence type
PubMed ID 12699381 Current protein Ligand is essential for catalysis
PubMed ID 8535786 Related protein: UniProt P80030 Ligand is essential for catalysis
PubMed ID 11368521 Related protein: UniProt P44432 Ligand is essential for catalysis
PubMed ID 8535786 Related protein: UniProt P80030 Structural similarity to homologue of known mechanism
PubMed ID 10521269 Related protein: UniProt P0A5Y6 Structural similarity to homologue of known mechanism
PubMed ID 10493822 Current protein Ligand is essential for catalysis
PubMed ID 10521269 Related protein: UniProt P0A5Y6 Ligand is essential for catalysis
PubMed ID 8535786 Related protein: UniProt P80030 Residue is positioned appropriately (ligand position known)
PubMed ID 10493822 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
TYRA 156 156Sidechain
Acid/baseSubstrate
Tyr 156 acts as the base that donates the proton to the enolate anion.
Evidence from paper Evidence concerns Evidence type
PubMed ID 8525786 Related protein: UniProt P80030 Structural similarity to homologue of known mechanism
PubMed ID 12699381 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 10493822 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 10521269 Related protein: UniProt P0A5Y6 Structural similarity to homologue of known mechanism
PubMed ID 10521269 Related protein: UniProt P0A5Y6 Conservation of residue
PubMed ID 8525786 Related protein: UniProt P80030 Conservation of residue
PubMed ID 8525786 Related protein: UniProt P80030 Residue is positioned appropriately (ligand position known)
PubMed ID 10521269 Related protein: UniProt P0A5Y6 Mutagenesis of residue

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
LYSA 163 163Sidechain
ElectrostaticTransition state
Lys 163 acts to stabilise the negatively charged transition state.
Evidence from paper Evidence concerns Evidence type
PubMed ID 8535786 Related protein: UniProt P80030 Conservation of residue
PubMed ID 10521269 Related protein: UniProt P0A5Y6 Mutagenesis of residue
PubMed ID 10493822 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 10521269 Related protein: UniProt P0A5Y6 Structural similarity to homologue of known mechanism
PubMed ID 8535786 Related protein: UniProt P80030 Residue is positioned appropriately (ligand position known)
PubMed ID 10521269 Related protein: UniProt P0A5Y6 Conservation of residue
PubMed ID 8535786 Related protein: UniProt P80030 Structural similarity to homologue of known mechanism
References:
1
Roles of tyrosine 158 and lysine 165 in the catalytic mechanism of InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis.
S. Parikh and D. P. Moynihan and G. Xiao and P. J. Tonge
Biochemistry 38, (41) 13623-34, (1999).
10521269
2
Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK.
M. A. Seefeld and W. H. Miller and K. A. Newlander and W. J. Burgess and W. E. DeWolf and P. A. Elkins and M. S. Head and D. R. Jakas and C. A. Janson and P. M. Keller and P. J. Manley and T. D. Moore and D. J. Payne and S. Pearson and B. J. Polizzi and X. Qiu and S. F. Rittenhouse and I. N. Uzinskas and N. G. Wallis and W. F. Huffman
J Med Chem 46, (9) 1627-35, (2003).
12699381
3
Enoyl-ACP reductase (FabI) of Haemophilus influenzae: steady-state kinetic mechanism and inhibition by triclosan and hexachlorophene.
J. Marcinkeviciene and W. Jiang and L. M. Kopcho and G. Locke and Y. Luo and R. A. Copeland
Arch Biochem Biophys 390, (1) 101-8, (2001).
11368521
4
Kinetic and structural characteristics of the inhibition of enoyl (acyl carrier protein) reductase by triclosan.
W. H. Ward and G. A. Holdgate and S. Rowsell and E. G. McLean and R. A. Pauptit and E. Clayton and W. W. Nichols and J. G. Colls and C. A. Minshull and D. A. Jude and A. Mistry and D. Timms and R. Camble and N. J. Hales and C. J. Britton and I. W. Taylor
Biochemistry 38, (38) 12514-25, (1999).
10493822
5
Common themes in redox chemistry emerge from the X-ray structure of oilseed rape (Brassica napus) enoyl acyl carrier protein reductase.
J. B. Rafferty and J. W. Simon and C. Baldock and P. J. Artymiuk and P. J. Baker and A. R. Stuitje and A. R. Slabas and D. W. Rice
Structure 3, (9) 927-38, (1995).
8535786
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