DB code: M00029

RLCP classification	1.13.11400.460 : Hydrolysis
CATH domain	3.10.170.20 : Elastase; domain 1	Catalytic domain
	3.90.132.10 : Leishmanolysin; domain 2	Catalytic domain
	2.10.55.10 : Leishmanolysin; domain 3
	2.30.34.10 : Leishmanolysin; domain 4
E.C.	3.4.24.36
CSA	1lml
M-CSA	1lml
MACiE

CATH domain	Related DB codes (homologues)

Uniprot Enzyme Name
UniprotKB	Protein name	Synonyms	MEROPS	Pfam
P08148	Leishmanolysin	EC 3.4.24.36 Cell surface protease Major surface glycoprotein Protein gp63 Promastigote surface endopeptidase Major surface protease	M08.001 (Metallo)	PF01457 (Peptidase_M8) [Graphical View]

KEGG enzyme name
leishmanolysin promastigote surface endopeptidase glycoprotein gp63 Leishmania metalloproteinase surface acid proteinase promastigote surface protease

UniprotKB: Accession Number	Entry name	Activity	Subunit	Subcellular location	Cofactor
P08148	GP63_LEIMA	Preference for hydrophobic residues at P1 and P1'' and basic residues at P2'' and P3''. A model nonapeptide is cleaved at -Ala-Tyr-\|-Leu-Lys-Lys-.		Cell membrane, Lipid-anchor, GPI-anchor.	Binds 1 zinc ion per subunit.

KEGG Pathways
Map code	Pathways	E.C.

Compound table
	Cofactors	Substrates			Products		Intermediates
KEGG-id	C00038	C00017	C00012	C00001	C00017	C00012
E.C.
Compound	Zinc	Protein	Peptide	H2O	Protein	Peptide
Type	heavy metal	peptide/protein	peptide/protein	H2O	peptide/protein	peptide/protein
ChEBI	29105 29105			15377 15377
PubChem	32051 32051			22247451 962 22247451 962

1lmlA01	Bound:_ZN	Unbound	Unbound		Unbound	Unbound
1lmlA02	Unbound	Unbound	Unbound		Unbound	Unbound
1lmlA03	Unbound	Unbound	Unbound		Unbound	Unbound
1lmlA04	Unbound	Unbound	Unbound		Unbound	Unbound

Reference for Active-site residues
resource	references	E.C.
PDB;1lml & Swiss-prot;P08148 & literature [4], [8], [11]

Active-site residues
PDB	Catalytic residues	Cofactor-binding residues	Modified residues	Main-chain involved in catalysis	Comment

1lmlA01	GLU 265	HIS 264;HIS 268(Zinc binding)
1lmlA02		HIS 334(Zinc binding)
1lmlA03
1lmlA04

References for Catalytic Mechanism
References	Sections	No. of steps in catalysis
[11]	p.1037-1040
[16]	Fig.1, p.158

References
[1]
Resource
Comments	GPI-ANCHOR.
Medline ID	91009116
PubMed ID	2145267
Journal	J Biol Chem
Year	1990
Volume	265
Pages	16955-64
Authors	Schneider P, Ferguson MA, McConville MJ, Mehlert A, Homans SW, Bordier C
Title	Structure of the glycosyl-phosphatidylinositol membrane anchor of the Leishmania major promastigote surface protease.
Related PDB
Related UniProtKB	P08148
[2]
Resource
Comments
Medline ID
PubMed ID	8314766
Journal	J Biol Chem
Year	1993
Volume	268
Pages	13994-4002
Authors	Webb JR, McMaster WR
Title	Molecular cloning and expression of a Leishmania major gene encoding a single-stranded DNA-binding protein containing nine "CCHC" zinc finger motifs.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID	8084652
Journal	Parasitology
Year	1994
Volume	108 Suppl
Pages	S29-36
Authors	McMaster WR, Morrison CJ, MacDonald MH, Joshi PB
Title	Mutational and functional analysis of the Leishmania surface metalloproteinase GP63: similarities to matrix metalloproteinases.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID	8519803
Journal	Biochim Biophys Acta
Year	1995
Volume	1253
Pages	199-207
Authors	Macdonald MH, Morrison CJ, McMaster WR
Title	Analysis of the active site and activation mechanism of the Leishmania surface metalloproteinase GP63.
Related PDB
Related UniProtKB
[5]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS), DISULFIDE BONDS, AND CARBOHYDRATE-LINKAGE SITES ASN-300; ASN-407 AND ASN-534.
Medline ID	95406217
PubMed ID	7675788
Journal	Proteins
Year	1995
Volume	22
Pages	58-66
Authors	Schlagenhauf E, Etges R, Metcalf P
Title	Crystallization and preliminary X-ray diffraction studies of leishmanolysin, the major surface metalloproteinase from Leishmania major.
Related PDB
Related UniProtKB	P08148
[6]
Resource
Comments
Medline ID
PubMed ID	8573078
Journal	Biochem J
Year	1996
Volume	313
Pages	455-66
Authors	Soteriadou KP, Tzinia AK, Panou-Pamonis E, Tsikaris V, Sakarellos-Daitsiotis M, Sakarellos C, Papapoulou Y, Matsas R
Title	Antigenicity and conformational analysis of the Zn(2+)-binding sites of two Zn(2+)-metalloproteases: Leishmania gp63 and mammalian endopeptidase-24.11.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID	11848831
Journal	Chem Rev
Year	1996
Volume	96
Pages	2375-2434
Authors	Lipscomb WN, Strater N
Title	Recent Advances in Zinc Enzymology.
Related PDB
Related UniProtKB
[8]
Resource
Comments	MUTAGENESIS OF TYR-254; HIS-264; GLU-265; HIS-268; ASN-300; ASN-407; ASN-534 AND ASN-577.
Medline ID
PubMed ID	8626468
Journal	J Biol Chem
Year	1996
Volume	271
Pages	7903-9
Authors	McGwire BS, Chang KP
Title	Posttranslational regulation of a Leishmania HEXXH metalloprotease (gp63). The effects of site-specific mutagenesis of catalytic, zinc binding, N-glycosylation, and glycosyl phosphatidylinositol addition sites on N-terminal end cleavage, intracellular stability, and extracellular exit.
Related PDB
Related UniProtKB	P08148
[9]
Resource
Comments
Medline ID
PubMed ID	9000250
Journal	Pept Res
Year	1996
Volume	9
Pages	240-7
Authors	Tsikaris V, Sakarellos C, Sakarellos-Daitsiotis M, Cung MT, Marraud M, Konidou G, Tzinia A, Soteriadou KP
Title	Use of sequential oligopeptide carriers (SOCn) in the design of potent Leishmania gp63 immunogenic peptides.
Related PDB
Related UniProtKB
[10]
Resource
Comments	CARBOHYDRATE-LINKAGE SITES ASN-307 AND ASN-400.
Medline ID
PubMed ID	9041519
Journal	Mol Biochem Parasitol
Year	1997
Volume	84
Pages	33-48
Authors	Funk VA, Thomas-Oates JE, Kielland SL, Bates PA, Olafson RW
Title	A unique, terminally glucosylated oligosaccharide is a common feature on Leishmania cell surfaces.
Related PDB
Related UniProtKB	P08148
[11]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (1.86 ANGSTROMS).
Medline ID	98416698
PubMed ID	9739094
Journal	Structure
Year	1998
Volume	6
Pages	1035-46
Authors	Schlagenhauf E, Etges R, Metcalf P
Title	The crystal structure of the Leishmania major surface proteinase leishmanolysin (gp63).
Related PDB	1lml
Related UniProtKB	P08148
[12]
Resource
Comments
Medline ID
PubMed ID	10464034
Journal	Exp Parasitol
Year	1999
Volume	93
Pages	7-22
Authors	Puentes F, Guzman F, Marin V, Alonso C, Patarroyo ME, Moreno A
Title	Leishmania: fine mapping of the Leishmanolysin molecule's conserved core domains involved in binding and internalization.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID	10924466
Journal	Genetics
Year	2000
Volume	155
Pages	1683-92
Authors	Alvarez-Valin F, Tort JF, Bernardi G
Title	Nonrandom spatial distribution of synonymous substitutions in the GP63 gene from Leishmania.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID	12137567
Journal	Biochem J
Year	2002
Volume	367
Pages	761-9
Authors	Corradin S, Ransijn A, Corradin G, Bouvier J, Delgado MB, Fernandez-Carneado J, Mottram JC, Vergeres G, Mauel J
Title	Novel peptide inhibitors of Leishmania gp63 based on the cleavage site of MARCKS (myristoylated alanine-rich C kinase substrate)-related protein.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID	14563532
Journal	Mol Biochem Parasitol
Year	2003
Volume	132
Pages	1-16
Authors	Yao C, Donelson JE, Wilson ME
Title	The major surface protease (MSP or GP63) of Leishmania sp. Biosynthesis, regulation of expression, and function.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID	12746556
Journal	Mol Biotechnol
Year	2003
Volume	24
Pages	157-202
Authors	Gomis-Ruth FX
Title	Structural aspects of the metzincin clan of metalloendopeptidases.
Related PDB
Related UniProtKB

Comments
This enzyme belongs to the peptidase family-M8. According to the literature [16], this enzyme is classified as a metzincin class zinc proteinase, which includes astacin (S00394 in EzCatDB), serralysin (D00236), adamalysin (S00399). However, the homologous family in the CATH classification of these enzymes (CATH 3.40.390.10) are different from that of this enzyme, although the strucutre of active site (residues 200-272) of this enzyme can be superimposed to those active sites. It suggests a distant evolutionarily relationships with these enzymes. According to the literature [11] & [16], this enzyme seems to have a similar mechanism to those of the above enzymes. Among them, adamalysin (S00399) and neutrophil collagenase (S00397) have got similar active sites, suggesting that this enzyme has the same reaction mechanism as those of these enzymes.

Comments

This enzyme belongs to the peptidase family-M8.
According to the literature [16], this enzyme is classified as a metzincin class zinc proteinase, which includes astacin (S00394 in EzCatDB), serralysin (D00236), adamalysin (S00399). However, the homologous family in the CATH classification of these enzymes (CATH 3.40.390.10) are different from that of this enzyme, although the strucutre of active site (residues 200-272) of this enzyme can be superimposed to those active sites. It suggests a distant evolutionarily relationships with these enzymes.
According to the literature [11] & [16], this enzyme seems to have a similar mechanism to those of the above enzymes. Among them, adamalysin (S00399) and neutrophil collagenase (S00397) have got similar active sites, suggesting that this enzyme has the same reaction mechanism as those of these enzymes.

Created	Updated
2005-10-20	2009-02-26