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Structural biology of S-adenosylmethionine decarboxylase

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA.
Amino Acids (Impact Factor: 3.65). 12/2009; 38(2):451-60. DOI: 10.1007/s00726-009-0404-y
Source: PubMed

ABSTRACT S-adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and a subject of many structural and biochemical investigations for anti-cancer and anti-parasitic therapy. The enzyme undergoes an internal serinolysis reaction as a post-translational modification to generate the active site pyruvoyl group for the decarboxylation process. The crystal structures of AdoMetDC from Homo sapiens, Solanum tuberosum, Thermotoga maritima, and Aquifex aeolicus have been determined. Numerous crystal structures of human AdoMetDC and mutants have provided insights into the mechanism of autoprocessing, putrescine activation, substrate specificity, and inhibitor design to the enzyme. The comparison of the human and potato enzyme with the T. maritima and A. aeolicus enzymes supports the hypothesis that the eukaryotic enzymes evolved by gene duplication and fusion. The residues implicated in processing and activity are structurally conserved in all forms of the enzyme, suggesting a divergent evolution of AdoMetDC.

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    • "To become active, the proenzyme undergoes an internal serinolysis, which causes cleavage of the proenzyme into two subunits (α and β) and also results in the formation of a pyruvoyl group at the N-terminus of the α-subunit (Fig. 4a) [62]. In mammals and yeast, Put stimulates AdoMetDC self-processing and activation [63] [64] [65]. "
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    • "Fusion of the aminopropyltransferase to AdoMetDC creates a problem because a side activity of AdoMetDC results eventually in irreversible transamidation of the AdoMetDC pyruvoyl cofactor, effectively killing the enzyme. The human AdoMetDC pyruvoyl group has been calculated to be transamidated after 15,000 turnover events (Bale & Ealick, 2010). Because of the transamidation, AdoMetDC has a relatively short activity half-life and so has to be synthesized at a relatively high rate. "
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