The Structure of Human α-Galactosidase A and Implications for Fabry Disease

Guce, A.I.; Garman, S.C.

doi:10.1007/978-90-481-9033-1_2

Cited by 3 publications

(3 citation statements)

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“…Three N-linked carbohydrates are found on the surface of the molecule, away from the location of the active site and away from the dimer interface. The carbohydrate residues attach to aspartic acid residues N139, N192 and N215 and extend from the surface of the molecule [ 245 ]. The enzyme folds into a three dimensional fold that gathers 15 residues into an active site configuration specific for α -galactosides.…”

Section: Reviewmentioning

confidence: 99%

“…Residues C142 and C172 make a disulfide bond. The two active sites in the dimer are separated by approximately 50 Å [ 245 ]. The α -galactosidase A enzyme uses a double displacement reaction mechanism, where two consecutive nucleophilic attacks on the anomeric carbon of the substrate lead to breakage of the glycosidic linkage with overall retention of the anomer of the product.…”

Section: Reviewmentioning

confidence: 99%

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Fabry disease

Germain

2010

Orphanet J Rare Dis

1,017

1,230

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Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers) and antiarrhythmic agents, whereas dialysis or renal transplantation are available for patients experiencing end-stage renal failure. With age, progressive damage to vital organ systems develops and at some point, organs may start to fail in functioning. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, as compared to the general population. While there is increasing evidence that long-term enzyme therapy can halt disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy drives research forward into active site specific chaperones.

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Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

Fabry disease

Germain

2010

Orphanet J Rare Dis

1,017

1,230

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“…Another new therapeutic option is offered by active site-specific chaperones (iminosugars). In Fabry disease many disease-causing mutations are missense mutations leading to unstable but still catalytically stable lysosomal protein [ 51 , 52 ]. Due to this unstable conformation, enzymes are unable to undergo trafficking to their appropriate location within the cell; mutated enzymes are retained in the endoplasmic reticulum and degraded because of their misfolded conformation [ 53 ].…”

Section: Dr H Toplak’s Diagnosismentioning

confidence: 99%

Clinical-Pathological Conference Series from the Medical University of Graz

Fabian

Schiller

Toplak

et al. 2017

Wien Klin Wochenschr

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Fabry’s disease: an example of cardiorenal syndrome type 5

et al. 2015

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Cardiorenal syndrome type 5 (CRS-5) includes conditions where there is a simultaneous involvement of the heart and kidney from a systemic disorder. This is a bilateral organ cross talk. Fabry's disease (FD) is a devastating progressive inborn error of metabolism with lysosomal glycosphingolipid deposition in variety of cell types, capillary endothelial cells, renal, cardiac and nerve cells. Basic effect is absent or deficient activity of lysosomal exoglycohydrolase a-galactosidase A. Renal involvement consists of proteinuria, isosthenuria, altered tubular function, presenting in second or third decade leading to azotemia and end-stage renal disease in third to fifth decade mainly due to irreversible changes to glomerular, tubular and vascular structures, especially highlighted by podocytes foot process effacement. Cardiac involvement consists of left ventricular hypertrophy, right ventricular hypertrophy, arrhythmias (sinus node and conduction system impairment), diastolic dysfunction, myocardial ischemia, infarction, transmural replacement fibrosis, congestive heart failure and cardiac death. Management of FD is based on enzymatic replacement therapy and control of renal (with anti-proteinuric agents such as angiotensin-converting enzyme inhibitors-and/or angiotensin II receptor blockers), brain (coated aspirin, clopidogrel and statin to prevent strokes) and heart complications (calcium channel blockers for ischemic cardiomyopathy, warfarin and amiodarone or cardioverter device for arrhythmias).

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The Structure of Human α-Galactosidase A and Implications for Fabry Disease

Cited by 3 publications

References 64 publications

Fabry disease

Fabry disease

Clinical-Pathological Conference Series from the Medical University of Graz

Fabry’s disease: an example of cardiorenal syndrome type 5

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