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Catalytic Site Atlas

CSA LITERATURE entry for 1f8m

E.C. nameisocitrate lyase
SpeciesMycobacterium tuberculosis (Bacteria)
E.C. Number (IntEnz)
CSA Homologues of 1f8mThere are 15 Homologs
CSA Entries With UniProtID P0A5H3
CSA Entries With EC Number
PDBe Entry 1f8m
PDBSum Entry 1f8m
MACiE Entry M0272

Literature Report

IntroductionIsocitrate lyase catalyses the reversible lysis of a C-C bond of isocitrate to form glycoxylate and succinate. The enzyme directs acetyl-CoA away from beta-oxidation of fatty acids into the glyoxylate shunt pathway, giving a net carbon gain. It plays a key role in the persistence of Mycobacterium tuberculosis within humans.
MechansimIn the reverse mechanism glyoxylate binds first to the enzyme, followed by succinate to form a tertiary complex. A Claisen condensation occurs, via the formation of an enolic intermediate to form the isocitrate product. The key step in the reaction is the deprotonation of the alpha proton of the carboxylate of succinate by Cys191, forming 4,4-di-hydroxy-3-butenoate. This intermediate then attacks the glyoxylate substrate. An unidentified residue is thought to act as a the general acid to the 6 carbon intermediate, while an oxyanion hole stabilises the negative charge on the intermediate.

Catalytic Sites for 1f8m

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
CysA191191macie:sideChainThe residue acts as a base towards the succinate substrate, abstracting the alpha proton and leading to the formation of the 4,4-di-hydroxy-3-butenoate intermediate.
HisA193193macie:sideChainThe residue is thought to act as a general base towards the catalytic Cys191, although crystallographic data suggests that proton abstraction may not be direct over the 5A separation.
ArgA228228macie:sideChainhe residue forms an oxyanion hole which stabilises the anionic intermediate.
HisA180180macie:sideChainThe residue forms an oxyanion hole which stabilises the anionic intermediate.

Literature References

Notes:Glu295 is stated in the original paper as acting as a general base, but it doesn't exist in the pdb file, so I have not entered it.
Sharma V
Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis.
Nat Struct Biol 2000 7 663-668
PubMed: 10932251