Sandbox Reserved 345

This Sandbox is Reserved from January 10, 2010, through April 10, 2011 for use in BCMB 307-Proteins course taught by Andrea Gorrell at the University of Northern British Columbia, Prince George, BC, Canada.

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S-Adenosylmethionine decarboxylaseS-Adenosylmethionine decarboxylase

S-Adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in the polyamine biosynthetic pathway, forming the amine decarboxylated S-adenosylmethionine It also aids in the synthesis of spermine and spermidine . Spermine and spermidine are polyamines that are essential growth factors and critical in cell differentiation . Their levels within cells are regulated by the amount of AdoMetDC available ref name="four"/>. Thus, AdoMetDC is tightly regulated in mammalian cells . Template:STRUCTURE 3cs9

Structure and FunctionStructure and Function

S-Adenosylmethionine decarboxylase is a (αβ)2 dimer, forming a four-layer αββα sandwich . The αβ monomers both have the same structure . The β chain consists of the residues 1-67 while the α chain contains the residues 68-329 . Each β sheet contains eight anti-parallel β strands . AdoMetDC has a very unique fold compared to other large β-sandwich structures as well as other pyruvoyl-dependent amino acid decarboxylases . The two β sheets are connected by only one covalent bond which allows them a large amount of flexibility to behave as independently folded domains that move with respect to each other . The α and β subunits are formed by an internal cleavage reaction . AdoMetDC belongs to a small class of decarboxylating enzymes that use as a prosthetic group a covalently bound pyruvate . The same cleavage reaction that forms the α and β subunits also converts a serine (Ser68) residue into the pyruvate . This self processing reaction occurs via a N to O acyl rearrangement . The pyruvoyl group is bound to the N-terminal of an α subunit . Decarboxylation of S-adenosylmethionine (AdoMet) to S-adenosyl-5’-(3-methylthiopropylamine) (dcAdoMet) is catalyzed using AdoMetDC . Spermidine is the receptor of the aminopropyl group from dcAdoMet forming spermine or spermidine . This is an early step in the pathway of polyamine biosynthesis of dcAdoMet, which commits it completely to this fate .

Mechanism:Mechanism:

Binding of AdoMet to its enzyme AdoMetDC is the first step and binding occurs through the pyruvate prosthetic group, reacting to give a Schiff base . The pyruvate then acts as an election sink, helping to break the carbon to carboxylic acid bond (C-COO-) resulting in a carbon dioxide (CO2) being eliminated . Protonation occurs at the R carbon of the product resulting in the release of dcAdoMet . This protonation also regenerates the pyruvate cofactor so that it is available and ready for another reaction .

ReferencesReferences

<refernces/> 1. Tolbert WD, Ekstrom JL, Mathews II, Secrist JA, Kapoor P, Pegg AE, Ealick SE. The structural basis for substrate specificity and inhibition of human S-Adenosylmethionine decarboxylase. Biochem. 2001 Jun 21;40:9484-94.

2.Xiong H, Stanley BA, Tekwani BL, Pegg AE. Processing of mammalian and plant S-Adenosylmethionine decarboxylase proenzymes. J Biological Chem. 1997 Mar 11;272(45):28342-48.

3.Ekstrom JL, Tolbert WD, Xiong H, Pegg AE, Ealick SE. Structure of a human S-Adenosylmethionine decarboxylase self-processing ester intermediate and mechanism of putrescine stimulation of processing as revealed by the H243A mutant. Biochem. 2001Jun 5;40(32):9495-504.

4.Tolbert WD, Zhang Y, Cottet SE, Bennett EM, Ekstrom JL, Pegg AE, Ealick SE. Mechanism of human S-Adenosylmethionine decarboxylase proenzyme processing as revealed by the structure of the S68A mutant. Biochem. 2003 Feb 7;42(8):2386-95.

5.Bale S, Brooks W, Hans JW, Mahesan AM, Guida WC, Ealick SE. Role of the sulfonium center in determining the ligand specificity of human S-Adenosylmethionine decarboxylase. Biochem. 2009 Jun 15;48(27):6423-30.

6.Xiong H, Stanley BA, Pegg AE. Role of cysteine-82 in the catalytic mechanism of human S-Adenosylmethionine. Biochem. 1999 Feb 4;38(8):2462-70.