DB code: S00399

RLCP classification	1.13.11400.460 : Hydrolysis
CATH domain	3.40.390.10 : Collagenase (Catalytic Domain)	Catalytic domain
E.C.	3.4.24.46
CSA
M-CSA
MACiE

CATH domain	Related DB codes (homologues)
3.40.390.10 : Collagenase (Catalytic Domain)	S00394 S00395 S00397 S00398 D00232 D00236 M00101

Uniprot Enzyme Name
UniprotKB	Protein name	Synonyms	MEROPS	Pfam
P34179	Zinc metalloproteinase adamalysin-2	EC 3.4.24.46 Adamalysin II Proteinase II	M12.141 (Metallo)	PF01421 (Reprolysin) [Graphical View]

KEGG enzyme name
adamalysin Crotalus adamanteus metalloendopeptidase proteinase I and II Crotalus adamanteus venom proteinase II adamalysin II

UniprotKB: Accession Number	Entry name	Activity	Subunit	Subcellular location	Cofactor
P34179	VMAD2_CROAD	Cleavage of 1-Phe-\|-Val-2, 5-His-\|-Leu-6, 14- Ala-\|-Leu-15, 15-Leu-\|-Tyr-16, and 16-Tyr-\|-Leu-17 of insulin B chain.	Monomer.	Secreted.	Binds 1 calcium ion per subunit. Binds 1 zinc ion per subunit.

KEGG Pathways
Map code	Pathways	E.C.

Compound table
	Cofactors		Substrates			Products		Intermediates
KEGG-id	C00076	C00038	C00017	C00012	C00001	C00017	C00012
E.C.
Compound	Calcium	Zinc	Protein	Peptide	H2O	Protein	Peptide
Type	divalent metal (Ca2+, Mg2+)	heavy metal	peptide/protein	peptide/protein	H2O	peptide/protein	peptide/protein
ChEBI	29108 29108	29105 29105			15377 15377
PubChem	271 271	32051 32051			22247451 962 22247451 962

1iagA	Bound:_CA	Bound:_ZN	Unbound	Unbound		Unbound	Unbound
2aigP	Bound:_CA	Bound:_ZN	Unbound	Unbound		Unbound	Unbound
3aigA	Bound:_CA	Bound:_ZN	Unbound	Unbound		Unbound	Unbound
4aigA	Bound:_CA	Bound:_ZN	Unbound	Unbound		Unbound	Unbound

Reference for Active-site residues
resource	references	E.C.
Swiss-prot;P34179

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

1iagA	GLU 143	HIS 142;HIS 146;HIS 152(Zinc binding)
2aigP	GLU 143	HIS 142;HIS 146;HIS 152(Zinc binding)
3aigA	GLU 143	HIS 142;HIS 146;HIS 152(Zinc binding)
4aigA	GLU 143	HIS 142;HIS 146;HIS 152(Zinc binding)

References for Catalytic Mechanism
References	Sections	No. of steps in catalysis
[1]	p.4155
[3]	p.530
[4]	p.832
[5]	p.381
[7]	p.320-321
[8]	p.285
[11]	p.1122-1123

References
[1]
Resource
Comments	X-ray crystallography (2.0 Angstroms)
Medline ID	94038897
PubMed ID	8223430
Journal	EMBO J
Year	1993
Volume	12
Pages	4151-7
Authors	Gomis-Ruth FX, Kress LF, Bode W
Title	First structure of a snake venom metalloproteinase: a prototype for matrix metalloproteinases/collagenases.
Related PDB	1iag
Related UniProtKB	P34179
[2]
Resource
Comments
Medline ID
PubMed ID	8243670
Journal	FEBS Lett
Year	1993
Volume	335
Pages	76-80
Authors	Grams F, Huber R, Kress LF, Moroder L, Bode W
Title	Activation of snake venom metalloproteinases by a cysteine switch-like mechanism.
Related PDB
Related UniProtKB
[3]
Resource
Comments	X-ray crystallography (2.0 Angstroms)
Medline ID	94275840
PubMed ID	8006965
Journal	J Mol Biol
Year	1994
Volume	239
Pages	513-44
Authors	Gomis-Ruth FX, Kress LF, Kellermann J, Mayr I, Lee X, Huber R, Bode W
Title	Refined 2.0 A X-ray crystal structure of the snake venom zinc-endopeptidase adamalysin II. Primary and tertiary structure determination, refinement, molecular structure and comparison with astacin, collagenase and thermolysin.
Related PDB
Related UniProtKB	P34179
[4]
Resource
Comments
Medline ID
PubMed ID	7663339
Journal	Protein Sci
Year	1995
Volume	4
Pages	823-40
Authors	Stocker W, Grams F, Baumann U, Reinemer P, Gomis-Ruth FX, McKay DB, Bode W
Title	The metzincins--topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID	8740360
Journal	Structure
Year	1996
Volume	4
Pages	375-86
Authors	Dhanaraj V, Ye QZ, Johnson LL, Hupe DJ, Ortwine DF, Dunbar JB Jr, Rubin JR, Pavlovsky A, Humblet C, Blundell TL
Title	X-ray structure of a hydroxamate inhibitor complex of stromelysin catalytic domain and its comparison with members of the zinc metalloproteinase superfamily.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID	9034190
Journal	Nature
Year	1997
Volume	385
Pages	729-33
Authors	Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP
Title	A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells.
Related PDB
Related UniProtKB
[7]
Resource
Comments	X-ray crystallography (2.0 Angstroms)
Medline ID	98089012
PubMed ID	9428736
Journal	FEBS Lett
Year	1997
Volume	418
Pages	319-22
Authors	Cirilli M, Gallina C, Gavuzzo E, Giordano C, Gomis-Ruth FX, Gorini B, Kress LF, Mazza F, Paradisi MP, Pochetti G, Politi V
Title	2 angstrom X-ray structure of adamalysin II complexed with a peptide phosphonate inhibitor adopting a retro-binding mode.
Related PDB	4aig
Related UniProtKB	P34179
[8]
Resource
Comments	X-ray crystallography (2.8 Angstroms)
Medline ID	98180398
PubMed ID	9521103
Journal	Protein Sci
Year	1998
Volume	7
Pages	283-92
Authors	Gomis-Ruth FX, Meyer EF, Kress LF, Politi V
Title	Structures of adamalysin II with peptidic inhibitors. Implications for the design of tumor necrosis factor alpha convertase inhibitors.
Related PDB	2aig 3aig
Related UniProtKB	P34179
[9]
Resource
Comments
Medline ID
PubMed ID	9784374
Journal	J Mol Biol
Year	1998
Volume	283
Pages	657-68
Authors	Gong W, Zhu X, Liu S, Teng M, Niu L
Title	Crystal structures of acutolysin A, a three-disulfide hemorrhagic zinc metalloproteinase from the snake venom of Agkistrodon acutus.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID	10708855
Journal	Biochim Biophys Acta
Year	2000
Volume	1477
Pages	146-56
Authors	Matsui T, Fujimura Y, Titani K
Title	Snake venom proteases affecting hemostasis and thrombosis.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID	12077431
Journal	Acta Crystallogr D Biol Crystallogr
Year	2002
Volume	58
Pages	1118-28
Authors	Huang KF, Chiou SH, Ko TP, Yuann JM, Wang AH
Title	The 1.35 A structure of cadmium-substituted TM-3, a snake-venom metalloproteinase from Taiwan habu: elucidation of a TNFalpha-converting enzyme-like active-site structure with a distorted octahedral geometry of cadmium.
Related PDB
Related UniProtKB

Comments
This enzyme belongs to the peptidase family-M12B. According to the papers [1], [3], & [7], zinc ion and carboxylate of Glu143 are proposed to polarize the zinc-bound water molecule for the nucleophilic attack on the scissile peptide bond during the catalysis. According to the literature [11], the pKa value of zinc-bound water in the homologous enzyme, carboxypeptidase A, lowered so as to play a functional role in the catalysis. In the homologous enzyme, the catalysis seems to proceed through the reaction in which the carboxylic group of the catalytic glutamate (corresponding to Glu143) acts as a general base to promote the nucleophilic attack by a water on the carbonyl group of scissile peptide bond. The stabilized tetrahedral intermediate then collapses with a requisite proton donation from the protonated glutamate (corresponding to Glu143) [11].

Comments

This enzyme belongs to the peptidase family-M12B.
According to the papers [1], [3], & [7], zinc ion and carboxylate of Glu143 are proposed to polarize the zinc-bound water molecule for the nucleophilic attack on the scissile peptide bond during the catalysis.
According to the literature [11], the pKa value of zinc-bound water in the homologous enzyme, carboxypeptidase A, lowered so as to play a functional role in the catalysis. In the homologous enzyme, the catalysis seems to proceed through the reaction in which the carboxylic group of the catalytic glutamate (corresponding to Glu143) acts as a general base to promote the nucleophilic attack by a water on the carbonyl group of scissile peptide bond. The stabilized tetrahedral intermediate then collapses with a requisite proton donation from the protonated glutamate (corresponding to Glu143) [11].

Created	Updated
2002-09-12	2009-02-26