3c6m
Crystal structure of human spermine synthase in complex with spermine and 5-methylthioadenosine
Structural highlights
DiseaseSPSY_HUMAN Defects in SMS are the cause of X-linked syndromic mental retardation Snyder-Robinson type (MRXSSR) [MIM:309583. Characterized by moderate intellectual deficit, hypotonia, an unsteady gait, osteoporosis, kyphoscoliosis and facial asymmetry. Transmission is X-linked recessive.[1] FunctionSPSY_HUMAN Catalyzes the production of spermine from spermidine and decarboxylated S-adenosylmethionine (dcSAM). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe crystal structures of two ternary complexes of human spermine synthase (EC 2.5.1.22), one with 5'-methylthioadenosine and spermidine and the other with 5'-methylthioadenosine and spermine, have been solved. They show that the enzyme is a dimer of two identical subunits. Each monomer has three domains: a C-terminal domain, which contains the active site and is similar in structure to spermidine synthase; a central domain made up of four beta-strands; and an N-terminal domain with remarkable structural similarity to S-adenosylmethionine decarboxylase, the enzyme that forms the aminopropyl donor substrate. Dimerization occurs mainly through interactions between the N-terminal domains. Deletion of the N-terminal domain led to a complete loss of spermine synthase activity, suggesting that dimerization may be required for activity. The structures provide an outline of the active site and a plausible model for catalysis. The active site is similar to those of spermidine synthases but has a larger substrate-binding pocket able to accommodate longer substrates. Two residues (Asp(201) and Asp(276)) that are conserved in aminopropyltransferases appear to play a key part in the catalytic mechanism, and this role was supported by the results of site-directed mutagenesis. The spermine synthase.5'-methylthioadenosine structure provides a plausible explanation for the potent inhibition of the reaction by this product and the stronger inhibition of spermine synthase compared with spermidine synthase. An analysis to trace possible evolutionary origins of spermine synthase is also described. Crystal structure of human spermine synthase: implications of substrate binding and catalytic mechanism.,Wu H, Min J, Zeng H, McCloskey DE, Ikeguchi Y, Loppnau P, Michael AJ, Pegg AE, Plotnikov AN J Biol Chem. 2008 Jun 6;283(23):16135-46. Epub 2008 Mar 26. PMID:18367445[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
