Crystal structure of beta-hexosaminidase B in complex with pyrimethamine, a potential pharmacological chaperone.

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Bateman KS, Cherney MM, Mahuran DJ, Tropak M, James MN

Crystal structure of beta-hexosaminidase B in complex with pyrimethamine, a potential pharmacological chaperone.

J Med Chem. 2011 Mar 10;54(5):1421-9. doi: 10.1021/jm101443u. Epub 2011 Jan 25.

PubMed ID

21265544 [ View in PubMed

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Abstract

beta-Hexosaminidases (beta-hex) are a group of glycosyl hydrolase isozymes that break down neutral and sialylated glycosphingolipids in the lysosomes, thereby preventing their buildup in neuronal cells. Some mutants of beta-hex have decreased folding stability that results in adult-onset forms of lysosomal storage diseases. However, prevention of the harmful accumulation of glycolipids only requires 10% of wild-type activity. Pyrimethamine (PYR) is a potential pharmacological chaperone that works by stabilizing these mutant enzymes sufficiently to allow more beta-hex to arrive in the lysosome, where it can carry out its function. An X-ray structure of the complex between human beta-hexosaminidase B (HexB) and PYR has been determined to 2.8 A. PYR binds to the active site of HexB where several favorable van der Waals contacts and hydrogen bonds are introduced. Small adjustments of the enzyme structure are required to accommodate the ligand, and details of the inhibition and stabilization properties of PYR are discussed.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Pyrimethamine	Beta-hexosaminidase subunit beta	Protein	Humans	Unknown	Not Available	Details