The Crystal Structure of Spermidine/Spermine N1-Acetyltransferase in Complex with Spermine Provides Insights into Substrate Binding and Catalysis,

Eric, Montemayor,; Hoffman, David W.

doi:10.1021/bi8009357

Cited by 27 publications

(41 citation statements)

References 37 publications

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“…The acetylation rate of N 1 AcTETA was approximately 10% at 10 mM compared with TETA at 10 mM using the spectrophotometric method (Coleman et al, 2004) (data not shown). Furthermore, we determined the kinetic values for acetylation of TETA using hSSAT1 to compare the properties of the human and mouse recombinant enzymes that show high structural homology (Hegde et al, 2007;Montemayor and Hoffman, 2008 (Weisell et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

Complex N-Acetylation of Triethylenetetramine

Cerrada-Gimenez¹,

Weisell²,

Hyvönen³

et al. 2011

Drug Metab Dispos

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Section: Resultsmentioning

confidence: 99%

Complex N-Acetylation of Triethylenetetramine

Cerrada-Gimenez¹,

Weisell²,

Hyvönen³

et al. 2011

Drug Metab Dispos

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“…By contrast, there are several acetyltransferases where the guanidine side chain of an arginine is positioned within 3 Å of the 3 0 -phosphoanion of bound CoA. These include spermine-spermidine acetyltransferase (Arg 142 and Arg 143 ) [39] and serotonin acetyltransferases (Arg 170 ) [40]. Both arginine and lysine residues readily undergo post-translational modification, including methylation, acetylation sumoylation and ubiquitination, which would be a novel mechanism for regulating acetyltransferase activity by altering AcCoA binding.…”

Section: Discussionmentioning

confidence: 99%

The role of lysine100 in the binding of acetylcoenzyme A to human arylamine N-acetyltransferase 1: Implications for other acetyltransferases

Minchin

Butcher

2015

Biochemical Pharmacology

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The arylamine N-acetyltransferases (NATs) catalyze the acetylation of aromatic and heterocyclic amines as well as hydrazines. All proteins in this family of enzymes utilize acetyl coenzyme A (AcCoA) as an acetyl donor, which initially binds to the enzyme and transfers an acetyl group to an active site cysteine. Here, we have investigated the role of a highly conserved amino acid (Lys(100)) in the enzymatic activity of human NAT1. Mutation of Lys(100) to either a glutamine or a leucine significantly increased the Ka for AcCoA without changing the Kb for the acetyl acceptor p-aminobenzoic acid. In addition, substrate inhibition was more marked with the mutant enzymes. Steady state kinetic analyzes suggested that mutation of Lys(100) to either leucine or glutamine resulted in a less stable enzyme-cofactor complex, which was not seen with a positively charged arginine at this position. When p-nitrophenylacetate was used as acetyl donor, no differences were seen between the wild-type and mutant enzymes because p-nitrophenylacetate is too small to interact with Lys(100) when bound to the active site. Using 3'-dephospho-AcCoA as the acetyl donor, kinetic data confirmed that Ly(100) interacts with the 3'-phosphoanion to stabilize the enzyme-cofactor complex. Mutation of Lys(100) decreases the affinity of AcCoA for the protein and increases the rate of CoA release. Crystal structures of several other unrelated acetyltransferases show a lysine or arginine residue within 3Å of the 3'-phosphoanion of AcCoA, suggesting that this mechanism for stabilizing the complex by the formation of a salt bridge may be widely applicable in nature.

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“…Crystal structures of the human and mouse SSAT protein have been obtained in the presence and absence of ligands including substrates and inhibitors (Fig. 3) [15-17]. These studies provide a good understanding of the reaction mechanism and the substrate specificity.…”

Section: Ssat: a Highly Regulated Rate-limiting Step In Polyamine Camentioning

confidence: 99%

Polyamine catabolism and disease

Casero

Pegg

2009

Biochemical Journal

331

318

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In addition to polyamine homeostasis, it has become increasingly clear that polyamine catabolism can play a dominant role in drug response, apoptosis, response to stressful stimuli, and contribute to the etiology of several pathological states, including cancer. The highly inducible enzymes spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMO), and, the generally constitutively expressed N1-acetylpolyamine oxidase (APAO), appear to play critical roles in many normal and disease processes. The dysregulation of polyamine catabolism frequently accompanies several disease states and suggests that such dysregulation may both provide useful insight into disease mechanism and provide unique drugable targets that can be exploited for therapeutic benefit. Each of these enzymes has the potential to alter polyamine homeostasis in response to multiple cell signals and the two oxidases produce the reactive oxygen species H2O2 and aldehydes, each with the potential to produce pathologies. The activity of SSAT has the potential to provide substrates for APAO or substrates for the polyamine exporter, thus reducing the intracellular polyamine concentration, the net effect of which depends on the magnitude and rate of any increase in SSAT. SSAT may also influence cellular metabolism via interaction with other proteins and by perturbing the content of acetyl CoA and ATP. The goal of this review is to cover those aspects of polyamine catabolism that have potential to impact disease etiology or treatment and to provide a solid background in this ever more exciting aspect of polyamine biology.

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The Crystal Structure of Spermidine/Spermine N¹-Acetyltransferase in Complex with Spermine Provides Insights into Substrate Binding and Catalysis^,

Cited by 27 publications

References 37 publications

Complex N-Acetylation of Triethylenetetramine

Complex N-Acetylation of Triethylenetetramine

The role of lysine100 in the binding of acetylcoenzyme A to human arylamine N-acetyltransferase 1: Implications for other acetyltransferases

Polyamine catabolism and disease

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