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Catalytic Site Atlas Version 2.2.12
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CSA entry for 1hr6
Original Entry
Title:
Hydrolase
Compound:
Mitochondrial processing peptidase alpha subunit
Mutant:
No
UniProt/Swiss-Prot:
P10507-MPPB_YEAST
P11914-MPPA_YEAST
EC Class:
3.4.24.64
Other CSA Entries:
Overview of all sites for 1hr6
Homologues of 1hr6
Entries for UniProt/Swiss-Prot: P10507
Entries for UniProt/Swiss-Prot: P11914
Entries for EC: 3.4.24.64
Other Databases:
PDB entry: 1hr6
PDBsum entry: 1hr6
UniProt/Swiss-Prot: P10507
UniProt/Swiss-Prot: P11914
IntEnz entry: 3.4.24.64
Literature Report:
Introduction:
Mitochondrial processing peptidase is a metalloendopeptidase that cleaves N-terminal signal sequences of proteins produced from nuclear information, transported from the cytosol to mitochondria. Cleavage of the signal sequence occurs at a single specific site.

The enzyme shows functional and structural convergent evolution of this protease family with that of thermolysin, which has a very similar active site.
Mechanism:
The enzymatic mechanism of mitochondrial processing peptidase is centred around the attack of a nucleophilic water molecule, polarised by Glu 73 and also activated by zinc, on the carbobyl carbon of the scissile bond. Zinc and the Glu residue stabilise the transition state. The Glu residue then donates the proton abstracted from the water molecule to the leaving amino group to facilitate the loss of the leaving group on collapse of the intermediate.
Sites:

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Found by:
Literature reference 
PsiBLAST alignment on 1hr7

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
GLUB 73 73Sidechain
Acid/baseSubstrate
Acid/baseWater
Acts as a general acid/base catalyst, activates and deprotonates water and protonates leaving group.
Evidence from paper Evidence concerns Evidence type
PubMed ID 6525336 Related protein: UniProt P00800 Computer modelling
PubMed ID 1570301 Current protein Conservation of residue
PubMed ID 11470436 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 11470436 Current protein Structural similarity to homologue of known mechanism
PubMed ID 7490252 Current protein Mutagenesis of residue
PubMed ID 6525336 Related protein: UniProt P00800 Residue is positioned appropriately (ligand position hypothetical)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ZNB 501 0Sidechain
ElectrostaticTransition state
ElectrostaticWater
ElectrostaticSubstrate
Activates water and the substrate and stabilises the transition state.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11470436 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 6525336 Related protein: UniProt P00800 Residue is positioned appropriately (ligand position hypothetical)
PubMed ID 6525336 Related protein: UniProt P00800 Computer modelling
PubMed ID 11470436 Current protein Structural similarity to homologue of known mechanism
References:
1
Structural basis of the Action of Thermolysin and Related Zinc Peptidases
B. W. Matthews
Acc. Chem. Res. 21, (9) 333-40, (1988).
No PubMed ID available
2
Crystal structures of mitochondrial processing peptidase reveal the mode for specific cleavage of import signal sequences.
A. B. Taylor and B. S. Smith and S. Kitada and K. Kojima and H. Miyaura and Z. Otwinowski and A. Ito and J. Deisenhofer
Structure (Camb) 9, (7) 615-25, (2001).
11470436
3
An interactive computer graphics study of thermolysin-catalyzed peptide cleavage and inhibition by N-carboxymethyl dipeptides.
D. G. Hangauer and A. F. Monzingo and B. W. Matthews
Biochemistry 23, (24) 5730-41, (1984).
6525336
4
An unusual active site identified in a family of zinc metalloendopeptidases.
A. B. Becker and R. A. Roth
Proc Natl Acad Sci U S A 89, (9) 3835-9, (1992).
1570301
5
A putative metal-binding site in the beta subunit of rat mitochondrial processing peptidase is essential for its catalytic activity.
S. Kitada and K. Shimokata and T. Niidome and T. Ogishima and A. Ito
J Biochem (Tokyo) 117, (6) 1148-50, (1995).
7490252
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