2jev
From Proteopedia
Crystal structure of human spermine,spermidine acetyltransferase in complex with a bisubstrate analog (N1-acetylspermine-S-CoA).
Structural highlights
DiseaseSAT1_HUMAN Defects in SAT1 may be a cause of keratosis follicularis spinulosa decalvans X-linked (KFSDX) [MIM:308800. A rare disorder affecting the skin and the eye. Affected men show thickening of the skin of the neck, ears, and extremities, especially the palms and soles, loss of eyebrows, eyelashes and beard, thickening of the eyelids with blepharitis and ectropion, and corneal degeneration.[1] [2] FunctionSAT1_HUMAN Enzyme which catalyzes the acetylation of polyamines. Substrate specificity: norspermidine = spermidine >> spermine > N(1)-acetylspermine > putrescine. This highly regulated enzyme allows a fine attenuation of the intracellular concentration of polyamines. Also involved in the regulation of polyamine transport out of cells. Acts on 1,3-diaminopropane, 1,5-diaminopentane, putrescine, spermidine (forming N(1)- and N(8)-acetylspermidine), spermine, N(1)-acetylspermidine and N(8)-acetylspermidine. 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 N1-acetylation of spermidine and spermine by spermidine/spermine acetyltransferase (SSAT) is a crucial step in the regulation of the cellular polyamine levels in eukaryotic cells. Altered polyamine levels are associated with a variety of cancers as well as other diseases, and key enzymes in the polyamine pathway, including SSAT, are being explored as potential therapeutic drug targets. We have expressed and purified human SSAT in Escherichia coli and characterized its kinetic and chemical mechanism. Initial velocity and inhibition studies support a random sequential mechanism for the enzyme. The bisubstrate analogue, N1-spermine-acetyl-coenzyme A, exhibited linear, competitive inhibition against both substrates with a true Ki of 6 nM. The pH-activity profile was bell-shaped, depending on the ionization state of two groups exhibiting apparent pKa values of 7.27 and 8.87. The three-dimensional crystal structure of SSAT with bound bisubstrate inhibitor was determined at 2.3 A resolution. The structure of the SSAT-spermine-acetyl-coenzyme A complex suggested that Tyr140 acts as general acid and Glu92, through one or more water molecules, acts as the general base during catalysis. On the basis of kinetic properties, pH dependence, and structural information, we propose an acid/base-assisted reaction catalyzed by SSAT, involving a ternary complex. Mechanistic and structural analysis of human spermidine/spermine N1-acetyltransferase.,Hegde SS, Chandler J, Vetting MW, Yu M, Blanchard JS Biochemistry. 2007 Jun 19;46(24):7187-95. Epub 2007 May 22. PMID:17516632[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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