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Biochemistry of Fabry Disease

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Fabry Disease

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Abstract

Fabry disease is a sphingolipid storage disorder resulting from a deficiency of the lysosomal hydrolase, α-galactosidase A. The deficiency leads to lysosomal accumulation of α-galactosidase A substrates, neutral glycosphingolipids with terminal α-galactosyl moieties, in multiple tissues. Globotriaosylceramide (Gb3Cer, CD77), the critical substrate of α-galactosidase A, is involved in cell signaling and associates itself with lipid rafts in the plasma membrane, where it also functions as a receptor for the Shiga-like toxins of E. Coli. Possible roles of Gb3Cer accumulation in the pathogenesis of Fabry disease, as well as biochemistry and function of minor α-galactosidase A substrates are discussed. There are two human lysosomal enzymes with the ability to hydrolyze substrates with terminal α-galactose, α-galactosidase A and α-N-acetylgalactosaminidase (NAGA). Both enzymes are active in vitro against saccharide, glycolipid and artificial substrates. α-N-acetylgalactosaminidase’s primary function appears to be hydrolysis of acetylated oligosaccharides and glycopeptides, while α-galactosidase A is the enzyme responsible for degradation of glycolipid substrates. α-Galactosidase A requires an activator protein, saposin B, for its activity in vivo. Properties of the above proteins and the biochemistry of their deficiencies in humans are also addressed.

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Acknowledgment

We thank Dr. Klaus Harzer and Dr. František Šmíd for critically commenting on the manuscript. The support of the Ministry of Education, Youth, and Sports of the Czech Republic (Grant No. MSM 0021620806) is gratefully acknowledged.

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  1. First Faculty of Medicine, Institute of Inherited Metabolic Disorders, Charles University, Prague and General University Hospital, Prague, Czech Republic

    Martin Hřebíček & Jana Ledvinová

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  1. Martin Hřebíček
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  2. Jana Ledvinová
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Correspondence to Martin Hřebíček .

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  1. , Shaare Zedek Medical Center, Gaucher Clinic, Bayit Street 12, Jerusalem, 91034, Israel

    Deborah Elstein

  2. , Shaare Zedek Medical Center, Genetics Unit, Bayit Street 12, Jerusalem, 91031, Israel

    Gheona Altarescu

  3. University of Mainz, Children's Hospital, Langenbeckstrasse 1, Mainz, 55131, Germany

    Michael Beck

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Hřebíček, M., Ledvinová, J. (2010). Biochemistry of Fabry Disease. In: Elstein, D., Altarescu, G., Beck, M. (eds) Fabry Disease. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9033-1_4

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