5w49 | pdb_00005w49
The crystal structure of human S-adenosylhomocysteine hydrolase (AHCY) bound to oxadiazole inhibitor
Structural highlights
Disease[SAHH_HUMAN] Defects in AHCY are the cause of hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency (HMAHCHD) [MIM:613752]. A metabolic disorder characterized by hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy.[1] [2] [3] [4] Function[SAHH_HUMAN] Adenosylhomocysteine is a competitive inhibitor of S-adenosyl-L-methionine-dependent methyl transferase reactions; therefore adenosylhomocysteinase may play a key role in the control of methylations via regulation of the intracellular concentration of adenosylhomocysteine.[5] Publication Abstract from PubMedS-adenosylhomocysteine hydrolase (AHCY) catalyzes the reversible hydrolysis of S-adenosylhomocysteine (SAH) to adenosine and l-homocysteine. This enzyme is frequently overexpressed in many tumor types and is considered to be a validated anti-tumor target. In order to enable the development of small molecule AHCY inhibitors as targeted cancer therapeutics we developed an assay based on a RapidFire high-throughput mass spectrometry detection system, which allows the direct measurement of AHCY enzymatic activity. This technique avoids many of the problems associate with the previously reported method of using a thiol-reactive fluorescence probes to measure AHCY activity. Screening of a approximately 500,000 compound library using this technique identified multiple SAH competitive hits. Co-crystal structures of the hit compounds complexed with AHCY were obtained showing that the compounds indeed bind in the SAH site of the enzyme. In addition, some hit compounds increased the SAH levels in HCT116 cells and showed growth inhibition. These compounds could be promising starting points for the optimization of cancer treatments. Identification of AHCY inhibitors using novel high-throughput mass spectrometry.,Uchiyama N, Dougan DR, Lawson JD, Kimura H, Matsumoto SI, Tanaka Y, Kawamoto T Biochem Biophys Res Commun. 2017 Sep 9;491(1):1-7. doi:, 10.1016/j.bbrc.2017.05.107. Epub 2017 May 19. PMID:28533090[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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