1mlz
From Proteopedia
(New page: 200px<br /><applet load="1mlz" size="450" color="white" frame="true" align="right" spinBox="true" caption="1mlz, resolution 2.15Å" /> '''Crystal Structure of...) |
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| - | [[Image:1mlz.gif|left|200px]]<br /><applet load="1mlz" size=" | + | [[Image:1mlz.gif|left|200px]]<br /><applet load="1mlz" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1mlz, resolution 2.15Å" /> | caption="1mlz, resolution 2.15Å" /> | ||
'''Crystal Structure of 7,8-Diaminopelargonic Acid Synthase in complex with the trans-isomer of amiclenomycin.'''<br /> | '''Crystal Structure of 7,8-Diaminopelargonic Acid Synthase in complex with the trans-isomer of amiclenomycin.'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The antibiotic amiclenomycin blocks the biosynthesis of biotin by | + | The antibiotic amiclenomycin blocks the biosynthesis of biotin by inhibiting the pyridoxal-phosphate-dependent enzyme diaminopelargonic acid synthase. Inactivation of the enzyme is stereoselective, i.e. the cis isomer of amiclenomycin is a potent inhibitor, whereas the trans isomer is much less reactive. The crystal structure of the complex of the holoenzyme and amiclenomycin at 1.8 A resolution reveals that the internal aldimine linkage between the cofactor and the side chain of the catalytic residue Lys-274 is broken. Instead, a covalent bond is formed between the 4-amino nitrogen of amiclenomycin and the C4' carbon atom of pyridoxal-phosphate. The electron density for the bound inhibitor suggests that aromatization of the cyclohexadiene ring has occurred upon formation of the covalent adduct. This process could be initiated by proton abstraction at the C4 carbon atom of the cyclohexadiene ring, possibly by the proximal side chain of Lys-274, leading to the tautomer Schiff base followed by the removal of the second allylic hydrogen. The carboxyl tail of the amiclenomycin moiety forms a salt link to the conserved residue Arg-391 in the substrate-binding site. Modeling suggests steric hindrance at the active site as the determinant of the weak inhibiting potency of the trans isomer. |
==About this Structure== | ==About this Structure== | ||
| - | 1MLZ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with TZA, NA and PLP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Adenosylmethionine--8-amino-7-oxononanoate_transaminase Adenosylmethionine--8-amino-7-oxononanoate transaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.62 2.6.1.62] Full crystallographic information is available from [http:// | + | 1MLZ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=TZA:'>TZA</scene>, <scene name='pdbligand=NA:'>NA</scene> and <scene name='pdbligand=PLP:'>PLP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Adenosylmethionine--8-amino-7-oxononanoate_transaminase Adenosylmethionine--8-amino-7-oxononanoate transaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.62 2.6.1.62] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MLZ OCA]. |
==Reference== | ==Reference== | ||
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[[Category: subclass ii]] | [[Category: subclass ii]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:56:32 2008'' |
Revision as of 11:56, 21 February 2008
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Crystal Structure of 7,8-Diaminopelargonic Acid Synthase in complex with the trans-isomer of amiclenomycin.
Overview
The antibiotic amiclenomycin blocks the biosynthesis of biotin by inhibiting the pyridoxal-phosphate-dependent enzyme diaminopelargonic acid synthase. Inactivation of the enzyme is stereoselective, i.e. the cis isomer of amiclenomycin is a potent inhibitor, whereas the trans isomer is much less reactive. The crystal structure of the complex of the holoenzyme and amiclenomycin at 1.8 A resolution reveals that the internal aldimine linkage between the cofactor and the side chain of the catalytic residue Lys-274 is broken. Instead, a covalent bond is formed between the 4-amino nitrogen of amiclenomycin and the C4' carbon atom of pyridoxal-phosphate. The electron density for the bound inhibitor suggests that aromatization of the cyclohexadiene ring has occurred upon formation of the covalent adduct. This process could be initiated by proton abstraction at the C4 carbon atom of the cyclohexadiene ring, possibly by the proximal side chain of Lys-274, leading to the tautomer Schiff base followed by the removal of the second allylic hydrogen. The carboxyl tail of the amiclenomycin moiety forms a salt link to the conserved residue Arg-391 in the substrate-binding site. Modeling suggests steric hindrance at the active site as the determinant of the weak inhibiting potency of the trans isomer.
About this Structure
1MLZ is a Single protein structure of sequence from Escherichia coli with , and as ligands. Active as Adenosylmethionine--8-amino-7-oxononanoate transaminase, with EC number 2.6.1.62 Full crystallographic information is available from OCA.
Reference
Structural basis for the inhibition of the biosynthesis of biotin by the antibiotic amiclenomycin., Sandmark J, Mann S, Marquet A, Schneider G, J Biol Chem. 2002 Nov 8;277(45):43352-8. Epub 2002 Sep 5. PMID:12218056
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