Sandbox Reserved 345

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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

PDB ID 1i7c

Drag the structure with the mouse to rotate
1i7c, resolution 2.40Å ()
Ligands: ,
Non-Standard Residues:
Activity: Adenosylmethionine decarboxylase, with EC number 4.1.1.50
Related: 1jen, 1i72, 1i79, 1i7b, 1i7m
Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml


S-Adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in the polyamine biosynthetic pathway, forming the amine decarboxylated S-adenosylmethionine [1][2] It also aids in the synthesis of spermine and spermidine [1][3][4]. Spermine and spermidine are polyamines that are essential growth factors and critical in cell differentiation [4][5]. Their levels within cells are regulated by the amount of AdoMetDC available [4]. Thus, AdoMetDC is tightly regulated in mammalian cells [1].

Structure and FunctionStructure and Function

S-Adenosylmethionine decarboxylase is a (αβ)2 , forming a four-layer , [1]. The αβ monomers both have the same structure [1]. The β chain consists of the residues 1-67 while the α chain contains the residues 68-329 [4]. Each β sheet contains eight anti-parallel β strands [1]. AdoMetDC has a very unique fold compared to other large β-sandwich structures as well as other pyruvoyl-dependent amino acid decarboxylases [1]. 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 [1]. The α and β subunits are formed by an internal cleavage reaction [1].

AdoMetDC belongs to a small class of decarboxylating enzymes that use as a prosthetic group a covalently bound [1][2]. The same cleavage reaction that forms the α and β subunits also converts a serine (Ser68) residue into the pyruvate [2][3][6]. This self processing reaction occurs via a N to O acyl rearrangement [3][4]. The pyruvoyl group is bound to the N-terminal of an α subunit [4][5]. Decarboxylation of S-adenosylmethionine (AdoMet) to S-adenosyl-5’-(3-methylthiopropylamine) (dcAdoMet) is catalyzed using AdoMetDC [2]. Spermidine is the receptor of the aminopropyl group from dcAdoMet forming spermine or spermidine [5]. This is an early step in the pathway of polyamine biosynthesis of dcAdoMet, which commits it completely to this fate [5].

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 [6]. 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 [6]. Protonation occurs at the R carbon of the product resulting in the release of dcAdoMet [6]. This protonation also regenerates the pyruvate cofactor so that it is available and ready for another reaction [6].

ReferencesReferences

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 Tolbert WD, Ekstrom JL, Mathews II, Secrist JA 3rd, Kapoor P, Pegg AE, Ealick SE. The structural basis for substrate specificity and inhibition of human S-adenosylmethionine decarboxylase. Biochemistry. 2001 Aug 14;40(32):9484-94. PMID:11583147
  2. ↑ 2.0 2.1 2.2 2.3 Xiong H, Stanley BA, Tekwani BL, Pegg AE. Processing of mammalian and plant S-adenosylmethionine decarboxylase proenzymes. J Biol Chem. 1997 Nov 7;272(45):28342-8. PMID:9353291
  3. ↑ 3.0 3.1 3.2 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. Biochemistry. 2001 Aug 14;40(32):9495-504. PMID:11583148
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 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. Biochemistry. 2003 Mar 4;42(8):2386-95. PMID:12600205 doi:10.1021/bi0268854
  5. ↑ 5.0 5.1 5.2 5.3 Bale S, Brooks W, Hanes JW, Mahesan AM, Guida WC, Ealick SE. Role of the Sulfonium Center in Determining the Ligand Specificity of Human S-Adenosylmethionine Decarboxylase. Biochemistry. 2009 Jun 15. PMID:19527050 doi:10.1021/bi900590m
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Xiong H, Stanley BA, Pegg AE. Role of cysteine-82 in the catalytic mechanism of human S-adenosylmethionine decarboxylase. Biochemistry. 1999 Feb 23;38(8):2462-70. PMID:10029540 doi:10.1021/bi9825201

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