2vfc: Difference between revisions

Revision as of 19:55, 21 February 2008

THE STRUCTURE OF MYCOBACTERIUM MARINUM ARYLAMINE N-ACETYLTRANSFERASE IN COMPLEX WITH COA

OverviewOverview

Arylamine N-acetyltransferase (NAT) enzymes are widespread in nature. They serve to acetylate xenobiotics and/or endogenous substrates using acetyl coenzyme A (CoA) as a cofactor. Conservation of the architecture of the NAT enzyme family from mammals to bacteria has been demonstrated by a series of prokaryotic NAT structures, together with the recently reported structure of human NAT1. We report here the cloning, purification, kinetic characterisation and crystallographic structure determination of NAT from Mycobacterium marinum, a close relative of the pathogenic Mycobacterium tuberculosis. We have also determined the structure of M. marinum NAT in complex with CoA, shedding the first light on cofactor recognition in prokaryotic NATs. Surprisingly, the principal CoA recognition site in M. marinum NAT is located some 30 A from the site of CoA recognition in the recently deposited structure of human NAT2 bound to CoA. The structure explains the Ping-Pong Bi-Bi reaction mechanism of NAT enzymes and suggests mechanisms by which the acetylated enzyme intermediate may be protected. Recognition of CoA in a much wider groove in prokaryotic NATs suggests that this subfamily may accommodate larger substrates than is the case for human NATs and may assist in the identification of potential endogenous substrates. It also suggests the cofactor-binding site as a unique subsite to target in drug design directed against NAT in mycobacteria.

About this StructureAbout this Structure

2VFC is a Single protein structure of sequence from Mycobacterium marinum with as ligand. Active as Arylamine N-acetyltransferase, with EC number 2.3.1.5 Known structural/functional Sites: and . Full crystallographic information is available from OCA.

ReferenceReference

Divergence of cofactor recognition across evolution: coenzyme A binding in a prokaryotic arylamine N-acetyltransferase., Fullam E, Westwood IM, Anderton MC, Lowe ED, Sim E, Noble ME, J Mol Biol. 2008 Jan 4;375(1):178-91. Epub 2007 Oct 13. PMID:18005984

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 ==Overview==
-Arylamine N-acetyltransferase (NAT) enzymes are widespread in nature. They, serve to acetylate xenobiotics and/or endogenous substrates using acetyl, coenzyme A (CoA) as a cofactor. Conservation of the architecture of the, NAT enzyme family from mammals to bacteria has been demonstrated by a, series of prokaryotic NAT structures, together with the recently reported, structure of human NAT1. We report here the cloning, purification, kinetic, characterisation and crystallographic structure determination of NAT from, Mycobacterium marinum, a close relative of the pathogenic Mycobacterium, tuberculosis. We have also determined the structure of M. marinum NAT in, complex with CoA, shedding the first light on cofactor recognition in, prokaryotic NATs. Surprisingly, the principal CoA recognition site in M., marinum NAT is located some 30 A from the site of CoA recognition in the, recently deposited structure of human NAT2 bound to CoA. The structure, explains the Ping-Pong Bi-Bi reaction mechanism of NAT enzymes and, suggests mechanisms by which the acetylated enzyme intermediate may be, protected. Recognition of CoA in a much wider groove in prokaryotic NATs, suggests that this subfamily may accommodate larger substrates than is the, case for human NATs and may assist in the identification of potential, endogenous substrates. It also suggests the cofactor-binding site as a, unique subsite to target in drug design directed against NAT in, mycobacteria.
+Arylamine N-acetyltransferase (NAT) enzymes are widespread in nature. They serve to acetylate xenobiotics and/or endogenous substrates using acetyl coenzyme A (CoA) as a cofactor. Conservation of the architecture of the NAT enzyme family from mammals to bacteria has been demonstrated by a series of prokaryotic NAT structures, together with the recently reported structure of human NAT1. We report here the cloning, purification, kinetic characterisation and crystallographic structure determination of NAT from Mycobacterium marinum, a close relative of the pathogenic Mycobacterium tuberculosis. We have also determined the structure of M. marinum NAT in complex with CoA, shedding the first light on cofactor recognition in prokaryotic NATs. Surprisingly, the principal CoA recognition site in M. marinum NAT is located some 30 A from the site of CoA recognition in the recently deposited structure of human NAT2 bound to CoA. The structure explains the Ping-Pong Bi-Bi reaction mechanism of NAT enzymes and suggests mechanisms by which the acetylated enzyme intermediate may be protected. Recognition of CoA in a much wider groove in prokaryotic NATs suggests that this subfamily may accommodate larger substrates than is the case for human NATs and may assist in the identification of potential endogenous substrates. It also suggests the cofactor-binding site as a unique subsite to target in drug design directed against NAT in mycobacteria.
 ==About this Structure==
-VFC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_marinum Mycobacterium marinum] with <scene name='pdbligand=COA:'>COA</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Arylamine_N-acetyltransferase Arylamine N-acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.5 2.3.1.5] Known structural/functional Sites: <scene name='pdbsite=AC1:Coa Binding Site For Chain B'>AC1</scene> and <scene name='pdbsite=AC2:Coa Binding Site For Chain A'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VFC OCA].
+VFC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_marinum Mycobacterium marinum] with <scene name='pdbligand=COA:'>COA</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Arylamine_N-acetyltransferase Arylamine N-acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.5 2.3.1.5] Known structural/functional Sites: <scene name='pdbsite=AC1:Coa+Binding+Site+For+Chain+B'>AC1</scene> and <scene name='pdbsite=AC2:Coa+Binding+Site+For+Chain+A'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VFC OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Mycobacterium marinum]]
 [[Category: Single protein]]
-[[Category: Anderton, M.C.]]
+[[Category: Anderton, M C.]]
 [[Category: Fullam, E.]]
-[[Category: Lowe, E.D.]]
+[[Category: Lowe, E D.]]
-[[Category: Noble, M.E.M.]]
+[[Category: Noble, M E.M.]]
 [[Category: Sim, E.]]
-[[Category: Westwood, I.M.]]
+[[Category: Westwood, I M.]]
 [[Category: COA]]
 [[Category: acetyl coa]]
@@ Line 28: / Line 28: @@
 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 11:36:16 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:55:30 2008''