2b5g
From Proteopedia
Wild Type SSAT- 1.7A structure
Structural highlights
Disease[SAT1_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] Function[SAT1_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 PubMedSpermidine/spermine N1-acetyltransferase (SSAT) is a key enzyme in the control of polyamine levels in human cells, as acetylation of spermidine and spermine triggers export or degradation. Increased intracellular polyamine levels accompany several types of cancers as well as other human diseases, and compounds that affect the expression, activity, or stability of SSAT are being explored as potential therapeutic drugs. We have expressed human SSAT from the cloned cDNA in Escherichia coli and have determined high-resolution structures of wild-type and mutant SSAT, as the free dimer and in binary and ternary complexes with CoA, acetyl-CoA (AcCoA), spermine, and the inhibitor N1,N11bis-(ethyl)-norspermine (BE-3-3-3). These structures show details of binding sites for cofactor, substrates, and inhibitor and provide a framework to understand enzymatic activity, mutations, and the action of potential drugs. Two dimer conformations were observed: a symmetric form with two open surface channels capable of binding substrate or cofactor, and an asymmetric form in which only one of the surface channels appears capable of binding and acetylating polyamines. SSAT was found to self-acetylate lysine-26 in the presence of AcCoA and absence of substrate, a reaction apparently catalzyed by AcCoA bound in the second channel of the asymmetric dimer. These unexpected and intriguing complexities seem likely to have some as yet undefined role in regulating SSAT activity or stability as a part of polyamine homeostasis. Sequence signatures group SSAT with proteins that appear to have thialysine Nepsilon-acetyltransferase activity. Structures of wild-type and mutant human spermidine/spermine N1-acetyltransferase, a potential therapeutic drug target.,Bewley MC, Graziano V, Jiang J, Matz E, Studier FW, Pegg AE, Coleman CS, Flanagan JM Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2063-8. Epub 2006 Feb 2. PMID:16455797[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Diamine N-acetyltransferase | Human | Bewley, M C | Burley, S K | Coleman, C S | Flanagan, J M | Graziano, V | Jiang, J S | Matz, E | Structural genomic | Pegg, A P | Studier, F W | NYSGXRC, New York SGX Research Center for Structural Genomics | PSI, Protein structure initiative | Transferase
