Structure of aspartoacylase, the brain enzyme impaired in Canavan disease.

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. Abstract Text:

Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. Deficiency in this activity leads to spongiform degeneration of the white matter of the brain and is the established cause of Canavan disease, a fatal progressive leukodystrophy affecting young children. We present crystal structures of recombinant human and rat aspartoacylase refined to 2.8- and 1.8-A resolution, respectively. The structures revealed that the N-terminal domain of aspartoacylase adopts a protein fold similar to that of zinc-dependent hydrolases related to carboxypeptidases A. The catalytic site of aspartoacylase shows close structural similarity to those of carboxypeptidases despite only 10-13% sequence identity between these proteins. About 100 C-terminal residues of aspartoacylase form a globular domain with a two-stranded beta-sheet linker that wraps around the N-terminal domain. The long channel leading to the active site is formed by the interface of the N- and C-terminal domains. The C-terminal domain is positioned in a way that prevents productive binding of polypeptides in the active site. The structures revealed that residues 158-164 may undergo a conformational change that results in opening and partial closing of the channel entrance. We hypothesize that the catalytic mechanism of aspartoacylase is closely analogous to that of carboxypeptidases. We identify residues involved in zinc coordination, and propose which residues may be involved in substrate binding and catalysis. The structures also provide a structural framework necessary for understanding the deleterious effects of many missense mutations of human aspartoacylase.

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. Publishing Authors By Initials

For similar inorganic chemicals: elements: metals, heavy: zinc research abstracts see: inorganic chemicals: elements: metals, heavy: zinc research

PUBMED ID PMID:

MEDLINE DATE:

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 104

Page Numbers: 456-61

Journal Abbreviation: Proc. Natl. Acad. Sci. U.S.A.

ISSN: 0027-8424

DAY: 28

MONTH: 12

YEAR: 2006

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7505876

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. Keywords Mesh Terms:

KEYWORDS: Zinc

MESH TERMS: chemistry

Chemical & Substance for Abstract: Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. Information

Substance Name: aspartoacylase

Registry Number: EC 3.5.1.15

Grant and Affiliation Information for Structure of aspartoacylase, the brain enzyme impaired in Canavan disease.

AFFILIATION: Center for Eukaryotic Structural Genomics, University of Wisconsin, Madison, WI 53706-1544, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: Y1-GM-1104

ACRONYM: GM

MEDLINETA: Proc Natl Acad Sci U S A

REFSOURCE: Proc Natl Acad Sci U S A. 2007 Jan 9;104

DATABASENAME:

ACCESSION NUMBER: 2I3C

Number Hits: 0

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease Related Publications

• Carrageenan/MIV-150 (PC-815), a combination microbicide.
• Curvilinear associations between benefit finding and psychosocial adjustment to breast cancer.
• Determinants of the variability of aflatoxin-albumin adduct levels in Ghanaians.
• Drifting blooms of the endemic filamentous brown alga Hincksia sordida at Noosa on the subtropical east Australian coast.
• Ethanol-related traits in mice selectively bred for differential sensitivity to methamphetamine-induced activation.
• GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol.
• Gravity: It's the law.
• Is 'alcoholism' genetically transmitted? And are there any implications for prevention?
• Optimization and evaluation of a coarse-grained model of protein motion using x-ray crystal data.
• Patent ductus arteriosus ligation in premature infants: who really benefits, and at what cost?
• Pathological skin picking in individuals with body dysmorphic disorder.
• Postchallenge glucose rises with increasing age even when glucose tolerance is normal.
• Relaxed selection among duplicate floral regulatory genes in Lamiales.
• Response of interleukin-1beta in the magnocellular system to salt-loading.
• Sensitivity to the locomotor-stimulant effects of ethanol and allopregnanolone: a quantitative trait locus study of common genetic influence.
• Social functioning in body dysmorphic disorder: assessment considerations.
• Structure and dynamics of UDP-glucose pyrophosphorylase from Arabidopsis thaliana with bound UDP-glucose and UTP.
• Structure of aspartoacylase, the brain enzyme impaired in Canavan disease.
• The limits of reductionism in medicine: could systems biology offer an alternative?
• The opportunity for canalization and the evolution of genetic networks.
• The role of structural prediction in rapid syntactic analysis.
• The time resolved fluorescence and anisotropy of subtilisins BPN' and Carlsberg.
• Total synthesis of (-)-dictyostatin.
• Tumor delineation using PET in head and neck cancers: threshold contouring and lesion volumes.
• Two- or four-hour lying deprivation on the behavior of lactating dairy cows.
• UPJ Obstruction in the Adult Population: Are Crossing Vessels Significant?
• Variation in pleiotropy and the mutational underpinnings of the G-matrix.
• Weight concerns in individuals with body dysmorphic disorder.
• X-ray crystal structures of the conserved hypothetical proteins from Arabidopsis thaliana gene loci At5g11950 and AT2g37210.
• [Survey of suicidal ideation and suicide attempts in outpatients at 50 general hospitals in Beijing]