Sandbox Reserved 345
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=S-Adenosylmethionine decarboxylase= | =S-Adenosylmethionine decarboxylase= | ||
| - | S-Adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in the polyamine biosynthetic pathway, forming the amine decarboxylated S-adenosylmethionine | + | S-Adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in the polyamine biosynthetic pathway, forming the amine decarboxylated S-adenosylmethionine <ref name="primary">PMID: 11583147</ref><ref name="two">PMID: 9353291</ref> It also aids in the synthesis of spermine and spermidine <ref name="primary"/><ref name="three">PMID: 11583148</ref><ref name="four">PMID: 12600205</ref>. Spermine and spermidine are polyamines that are essential growth factors and critical in cell differentiation <ref name="four"/><ref name="five">PMID: 19527050</ref>. Their levels within cells are regulated by the amount of AdoMetDC available ref name="four"/>. Thus, AdoMetDC is tightly regulated in mammalian cells <ref name="primary"/>. |
{{STRUCTURE_3cs9|PDB=3cs9|SCENE=Sandbox_Reserved_345/Begining/1}} | {{STRUCTURE_3cs9|PDB=3cs9|SCENE=Sandbox_Reserved_345/Begining/1}} | ||
==Structure and Function== | ==Structure and Function== | ||
| - | S-Adenosylmethionine decarboxylase is a (αβ)2 dimer, forming a four-layer αββα sandwich | + | S-Adenosylmethionine decarboxylase is a (αβ)2 dimer, forming a four-layer αββα sandwich <ref name="primary"/>. The αβ monomers both have the same structure <ref name="primary"/>. The β chain consists of the residues 1-67 while the α chain contains the residues 68-329 <ref name="four"/>. Each β sheet contains eight anti-parallel β strands <ref name="primary"/>. AdoMetDC has a very unique fold compared to other large β-sandwich structures as well as other pyruvoyl-dependent amino acid decarboxylases <ref name="primary"/>. 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 <ref name="primary"/>. The α and β subunits are formed by an internal cleavage reaction <ref name="primary"/>. |
| - | AdoMetDC belongs to a small class of decarboxylating enzymes that use as a prosthetic group a covalently bound pyruvate | + | AdoMetDC belongs to a small class of decarboxylating enzymes that use as a prosthetic group a covalently bound pyruvate <ref name="primary"/><ref name="two"/>. The same cleavage reaction that forms the α and β subunits also converts a serine (Ser68) residue into the pyruvate <ref name="two"/><ref name="three"/><ref name="six">PMID: 10029540</ref>. This self processing reaction occurs via a N to O acyl rearrangement <ref name="three"/><ref name="four"/>. The pyruvoyl group is bound to the N-terminal of an α subunit <ref name="four"/><ref name="five"/>. |
| - | Decarboxylation of S-adenosylmethionine (AdoMet) to S-adenosyl-5’-(3-methylthiopropylamine) (dcAdoMet) is catalyzed using AdoMetDC | + | Decarboxylation of S-adenosylmethionine (AdoMet) to S-adenosyl-5’-(3-methylthiopropylamine) (dcAdoMet) is catalyzed using AdoMetDC <ref name="two"/>. Spermidine is the receptor of the aminopropyl group from dcAdoMet forming spermine or spermidine <ref name="five"/>. This is an early step in the pathway of polyamine biosynthesis of dcAdoMet, which commits it completely to this fate <ref name="five"/>. |
==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 | + | 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 <ref name="six"/>. 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 <ref name="six"/>. Protonation occurs at the R carbon of the product resulting in the release of dcAdoMet <ref name="six"/>. This protonation also regenerates the pyruvate cofactor so that it is available and ready for another reaction <ref name="six"/>. |
==References== | ==References== | ||
| - | 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. | + | <refernces/> |
| - | 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. | + | 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. |
| - | 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. | + | 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. |
| - | 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. | + | 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. | ||
Revision as of 06:47, 4 April 2011
| 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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Contents |
S-Adenosylmethionine decarboxylase
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 ref name="four"/>. Thus, AdoMetDC is tightly regulated in mammalian cells [1]. Template:STRUCTURE 3cs9
Structure and Function
S-Adenosylmethionine decarboxylase is a (αβ)2 dimer, forming a four-layer αββα sandwich [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 pyruvate [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:
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].
References
<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.
