Leishmanolysin
Leishmania is a protozoan parasite transmitted from sandfly vector to human and other mammalian hosts causing chronic infections. It exists as extracellular promastigotes within sandflies and intracellular amastigotes within macrophage cells of mammals. Leishmanolysin is the major protein component of the Leishmania promastigote surface. It is characterised as a zinc metalloproteinase containing a glycosyl phosphatidyl inositol membrane anchor. It is an endopeptidase cleaving a variety of substrate. Its role in the life cycle Leishmania remains to be established.
Reference Protein and Structure
- Sequence
-
P08148
(3.4.24.36)
(Sequence Homologues) (PDB Homologues)
- Biological species
-
Leishmania major (Leishmania)
- PDB
-
1lml
- LEISHMANOLYSIN
(1.86 Å)
- Catalytic CATH Domains
-
3.10.170.20
3.90.132.10
(see all for 1lml)
- Cofactors
- Zinc(2+) (1)
Enzyme Reaction (EC:3.4.24.36)
Enzyme Mechanism
Introduction
Leishmanolysin consists of HEXXH motif which is common in all zinc metalloproteinase, so it was proposed that it shares the same mechanism as the other zinc metalloproteinases such as thermolysin. Glu265, acting in conjunction with Zn2+ ion to deprotonate and activate a water molecule. The activated water molecule acts as a nucleophile to attack the carbonyl of the peptide bond. Zn2+ stabilises the transition state by interacting with the negative charged carbonyl oxygen atom of the tetrahedral intermediate.
Catalytic Residues Roles
UniProt | PDB* (1lml) | ||
His264, His268, His334 | His264(165)A, His268(169)A, His334(235)A | Forms part of the Zinc binding site. | metal ligand |
Glu265 | Glu265(166)A | It acts as a base to deprotonate a water molecule to allow its nucleophilic attack on the peptide bond. | proton shuttle (general acid/base) |
Chemical Components
References
- Schlagenhauf E et al. (1998), Structure, 6, 1035-1046. The crystal structure of the Leishmania major surface proteinase leishmanolysin (gp63). DOI:10.1016/s0969-2126(98)00104-x. PMID:9739094.
- Macdonald MH et al. (1995), Biochim Biophys Acta, 1253, 199-207. Analysis of the active site and activation mechanism of the Leishmania surface metalloproteinase GP63. DOI:10.1016/0167-4838(95)00155-5. PMID:8519803.
Catalytic Residues Roles
Residue | Roles |
---|---|
Glu265(166)A | proton shuttle (general acid/base) |
His264(165)A | metal ligand |
His268(169)A | metal ligand |
His334(235)A | metal ligand |