2bfc
From Proteopedia
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==Overview== | ==Overview== | ||
| - | The dehydrogenase/decarboxylase (E1b) component of the 4 MD human | + | The dehydrogenase/decarboxylase (E1b) component of the 4 MD human branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is a thiamin diphosphate (ThDP)-dependent enzyme. We have determined the crystal structures of E1b with ThDP bound intermediates after decarboxylation of alpha-ketoacids. We show that a key tyrosine residue in the E1b active site functions as a conformational switch to reduce the reactivity of the ThDP cofactor through interactions with its thiazolium ring. The intermediates do not assume the often-postulated enamine state, but likely a carbanion state. The carbanion presumably facilitates the second E1b-catalyzed reaction, involving the transfer of an acyl moiety from the intermediate to a lipoic acid prosthetic group in the transacylase (E2b) component of the BCKDC. The tyrosine switch further remodels an E1b loop region to promote E1b binding to E2b. Our results illustrate the versatility of the tyrosine switch in coordinating the catalytic events in E1b by modulating the reactivity of reaction intermediates. |
==Disease== | ==Disease== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Brautigam, C | + | [[Category: Brautigam, C A.]] |
| - | [[Category: Chuang, D | + | [[Category: Chuang, D T.]] |
| - | [[Category: Chuang, J | + | [[Category: Chuang, J L.]] |
[[Category: Machius, M.]] | [[Category: Machius, M.]] | ||
| - | [[Category: Tomchick, D | + | [[Category: Tomchick, D R.]] |
| - | [[Category: Wynn, R | + | [[Category: Wynn, R M.]] |
[[Category: GOL]] | [[Category: GOL]] | ||
[[Category: K]] | [[Category: K]] | ||
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[[Category: thiamine diphosphate]] | [[Category: thiamine diphosphate]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:37:12 2008'' |
Revision as of 14:37, 21 February 2008
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REACTIVITY MODULATION OF HUMAN BRANCHED-CHAIN ALPHA-KETOACID DEHYDROGENASE BY AN INTERNAL MOLECULAR SWITCH
Contents |
Overview
The dehydrogenase/decarboxylase (E1b) component of the 4 MD human branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is a thiamin diphosphate (ThDP)-dependent enzyme. We have determined the crystal structures of E1b with ThDP bound intermediates after decarboxylation of alpha-ketoacids. We show that a key tyrosine residue in the E1b active site functions as a conformational switch to reduce the reactivity of the ThDP cofactor through interactions with its thiazolium ring. The intermediates do not assume the often-postulated enamine state, but likely a carbanion state. The carbanion presumably facilitates the second E1b-catalyzed reaction, involving the transfer of an acyl moiety from the intermediate to a lipoic acid prosthetic group in the transacylase (E2b) component of the BCKDC. The tyrosine switch further remodels an E1b loop region to promote E1b binding to E2b. Our results illustrate the versatility of the tyrosine switch in coordinating the catalytic events in E1b by modulating the reactivity of reaction intermediates.
Disease
Known diseases associated with this structure: Maple syrup urine disease, type Ia OMIM:[608348], Maple syrup urine disease, type Ib OMIM:[248611]
About this Structure
2BFC is a Protein complex structure of sequences from Homo sapiens with , , and as ligands. Active as 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring), with EC number 1.2.4.4 Known structural/functional Site: . Full crystallographic information is available from OCA.
Reference
A versatile conformational switch regulates reactivity in human branched-chain alpha-ketoacid dehydrogenase., Machius M, Wynn RM, Chuang JL, Li J, Kluger R, Yu D, Tomchick DR, Brautigam CA, Chuang DT, Structure. 2006 Feb;14(2):287-98. PMID:16472748
Page seeded by OCA on Thu Feb 21 16:37:12 2008
Categories: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) | Homo sapiens | Protein complex | Brautigam, C A. | Chuang, D T. | Chuang, J L. | Machius, M. | Tomchick, D R. | Wynn, R M. | GOL | K | MN | TZD | Acylation | Branched-chain | Conformational switch | Ketoacid dehydrogenase | Maple syrup urine disease | Multi-enzyme complex | Oxidative decarboxylation | Oxidoreductase | Phosphorylation | Reactivity | Thiamine diphosphate
