PDBsum entry 2o4h

Hydrolase

PDB id

2o4h

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Contents

			Protein chain

					301 a.a. *

			Ligands

					AS9 ×2

			Metals

					_ZN ×2

			Waters ×69

* Residue conservation analysis

PDB id:

2o4h

Links

Name:

Hydrolase

Title:

Human brain aspartoacylase complex with intermediate analog (n- phosphonomethyl-l-aspartate)

Structure:

Aspartoacylase. Chain: a, b. Synonym: aminoacylase-2, acy-2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: brain. Gene: aspa, acy2, asp. Expressed in: pichia pastoris. Expression_system_taxid: 4922.

Resolution:

2.70Å

R-factor:

0.205

R-free:

0.271

Authors:

J.Le Coq,A.Pavlovsky,R.Sanishvili,R.E.Viola

Key ref:

J.Le Coq et al. (2008). Examination of the mechanism of human brain aspartoacylase through the binding of an intermediate analogue. Biochemistry, 47, 3484-3492. PubMed id: 18293939

Date:

04-Dec-06

Release date:

06-Nov-07

PROCHECK

	Headers

	References

Protein chains

P45381 (ACY2_HUMAN) - Aspartoacylase from Homo sapiens

Seq: Struc:					313 a.a. 301 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.3.5.1.15 - aspartoacylase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

an N-acyl-L-aspartate + H2O = a carboxylate + L-aspartate

N-acyl-L-aspartate

H2O

carboxylate

L-aspartate
Bound ligand (Het Group name = AS9)
matches with 69.23% similarity

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

	Biochemistry 47:3484-3492 (2008)
PubMed id: 18293939

Examination of the mechanism of human brain aspartoacylase through the binding of an intermediate analogue.
J.Le Coq, A.Pavlovsky, R.Malik, R.Sanishvili, C.Xu, R.E.Viola.

ABSTRACT

Canavan disease is a fatal neurological disorder caused by the malfunctioning of a single metabolic enzyme, aspartoacylase, that catalyzes the deacetylation of N-acetyl-L-aspartate to produce L-aspartate and acetate. The structure of human brain aspartoacylase has been determined in complex with a stable tetrahedral intermediate analogue, N-phosphonomethyl-L-aspartate. This potent inhibitor forms multiple interactions between each of its heteroatoms and the substrate binding groups arrayed within the active site. The binding of the catalytic intermediate analogue induces the conformational ordering of several substrate binding groups, thereby setting up the active site for catalysis. The highly ordered binding of this inhibitor has allowed assignments to be made for substrate binding groups and provides strong support for a carboxypeptidase-type mechanism for the hydrolysis of the amide bond of the substrate, N-acetyl- l-aspartate.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21095151

S.Zano, R.Malik, S.Szucs, R.Matalon, and R.E.Viola (2011).
Modification of aspartoacylase for potential use in enzyme replacement therapy for the treatment of Canavan disease.

Mol Genet Metab, 102, 176-180.

20921362

J.M.Hsieh, K.Tsirulnikov, M.R.Sawaya, N.Magilnick, N.Abuladze, I.Kurtz, J.Abramson, and A.Pushkin (2010).
Structures of aminoacylase 3 in complex with acetylated substrates.

Proc Natl Acad Sci U S A, 107, 17962-17967.

PDB codes:

3nfz 3nh4 3nh5 3nh8

19362172

K.Tsirulnikov, N.Abuladze, D.Newman, S.Ryazantsev, T.Wolak, N.Magilnick, M.C.Koag, I.Kurtz, and A.Pushkin (2009).
Mouse aminoacylase 3: a metalloenzyme activated by cobalt and nickel.

Biochim Biophys Acta, 1794, 1049-1057.

19319678

M.H.Baslow, and D.N.Guilfoyle (2009).
Are astrocytes the missing link between lack of brain aspartoacylase activity and the spongiform leukodystrophy in canavan disease?

Neurochem Res, 34, 1523-1534.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.