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| - | [[Image:2bfc.gif|left|200px]]<br /><applet load="2bfc" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2bfc, resolution 1.64Å" /> | |
| - | '''REACTIVITY MODULATION OF HUMAN BRANCHED-CHAIN ALPHA-KETOACID DEHYDROGENASE BY AN INTERNAL MOLECULAR SWITCH'''<br /> | |
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| - | ==Overview== | + | ==Reactivity modulation of human branched-chain alpha-ketoacid dehydrogenase by an internal molecular switch== |
| - | 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. | + | <StructureSection load='2bfc' size='340' side='right'caption='[[2bfc]], [[Resolution|resolution]] 1.64Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2bfc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BFC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BFC FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.64Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=TZD:2-{3-[(4-AMINO-2-METHYLPYRIMIDIN-5-YL)METHYL]-4-METHYL-2-OXO-2,3-DIHYDRO-1,3-THIAZOL-5-YL}ETHYL+TRIHYDROGEN+DIPHOSPHATE'>TZD</scene></td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2bfc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bfc OCA], [https://pdbe.org/2bfc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2bfc RCSB], [https://www.ebi.ac.uk/pdbsum/2bfc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2bfc ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/ODBA_HUMAN ODBA_HUMAN] Defects in BCKDHA are a cause of maple syrup urine disease type IA (MSUD1A) [MIM:[https://omim.org/entry/248600 248600]. MSUD is an autosomal recessive disorder characterized by mental and physical retardation, feeding problems, and a maple syrup odor to the urine.<ref>PMID:2060625</ref> <ref>PMID:8037208</ref> <ref>PMID:2703538</ref> <ref>PMID:2241958</ref> <ref>PMID:1867199</ref> <ref>PMID:1885764</ref> <ref>PMID:8161368</ref> <ref>PMID:7883996</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/ODBA_HUMAN ODBA_HUMAN] The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3). |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bf/2bfc_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2bfc ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | 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==
| + | 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<ref>PMID:16472748</ref> |
| - | Known diseases associated with this structure: Maple syrup urine disease, type Ia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608348 608348]], Maple syrup urine disease, type Ib OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=248611 248611]]
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 2BFC is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with K, MN, TZD and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/3-methyl-2-oxobutanoate_dehydrogenase_(2-methylpropanoyl-transferring) 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.2.4.4 1.2.4.4] Known structural/functional Site: <scene name='pdbsite=AC1:Gol Binding Site For Chain B'>AC1</scene>. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2BFC OCA].
| + | </div> |
| | + | <div class="pdbe-citations 2bfc" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Reference== | + | ==See Also== |
| - | 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16472748 16472748]
| + | *[[2-oxoisovalerate dehydrogenase 3D structures|2-oxoisovalerate dehydrogenase 3D structures]] |
| - | [[Category: 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)]] | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Protein complex]] | + | [[Category: Large Structures]] |
| - | [[Category: Brautigam, C.A.]] | + | [[Category: Brautigam CA]] |
| - | [[Category: Chuang, D.T.]] | + | [[Category: Chuang DT]] |
| - | [[Category: Chuang, J.L.]] | + | [[Category: Chuang JL]] |
| - | [[Category: Machius, M.]] | + | [[Category: Machius M]] |
| - | [[Category: Tomchick, D.R.]] | + | [[Category: Tomchick DR]] |
| - | [[Category: Wynn, R.M.]] | + | [[Category: Wynn RM]] |
| - | [[Category: GOL]]
| + | |
| - | [[Category: K]]
| + | |
| - | [[Category: MN]]
| + | |
| - | [[Category: TZD]]
| + | |
| - | [[Category: acylation]]
| + | |
| - | [[Category: branched-chain]]
| + | |
| - | [[Category: conformational switch]]
| + | |
| - | [[Category: ketoacid dehydrogenase]]
| + | |
| - | [[Category: maple syrup urine disease]]
| + | |
| - | [[Category: multi-enzyme complex]]
| + | |
| - | [[Category: oxidative decarboxylation]]
| + | |
| - | [[Category: oxidoreductase]]
| + | |
| - | [[Category: phosphorylation]]
| + | |
| - | [[Category: reactivity]]
| + | |
| - | [[Category: thiamine diphosphate]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Dec 18 18:45:00 2007''
| + | |
| Structural highlights
Disease
ODBA_HUMAN Defects in BCKDHA are a cause of maple syrup urine disease type IA (MSUD1A) [MIM:248600. MSUD is an autosomal recessive disorder characterized by mental and physical retardation, feeding problems, and a maple syrup odor to the urine.[1] [2] [3] [4] [5] [6] [7] [8]
Function
ODBA_HUMAN The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3).
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
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[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Dariush N, Fisher CW, Cox RP, Chuang DT. Structure of the gene encoding the entire mature E1 alpha subunit of human branched-chain alpha-keto acid dehydrogenase complex. FEBS Lett. 1991 Jun 17;284(1):34-8. PMID:2060625
- ↑ Chuang JL, Fisher CR, Cox RP, Chuang DT. Molecular basis of maple syrup urine disease: novel mutations at the E1 alpha locus that impair E1(alpha 2 beta 2) assembly or decrease steady-state E1 alpha mRNA levels of branched-chain alpha-keto acid dehydrogenase complex. Am J Hum Genet. 1994 Aug;55(2):297-304. PMID:8037208
- ↑ Zhang B, Edenberg HJ, Crabb DW, Harris RA. Evidence for both a regulatory mutation and a structural mutation in a family with maple syrup urine disease. J Clin Invest. 1989 Apr;83(4):1425-9. PMID:2703538 doi:http://dx.doi.org/10.1172/JCI114033
- ↑ Matsuda I, Nobukuni Y, Mitsubuchi H, Indo Y, Endo F, Asaka J, Harada A. A T-to-A substitution in the E1 alpha subunit gene of the branched-chain alpha-ketoacid dehydrogenase complex in two cell lines derived from Menonite maple syrup urine disease patients. Biochem Biophys Res Commun. 1990 Oct 30;172(2):646-51. PMID:2241958
- ↑ Fisher CR, Fisher CW, Chuang DT, Cox RP. Occurrence of a Tyr393----Asn (Y393N) mutation in the E1 alpha gene of the branched-chain alpha-keto acid dehydrogenase complex in maple syrup urine disease patients from a Mennonite population. Am J Hum Genet. 1991 Aug;49(2):429-34. PMID:1867199
- ↑ Fisher CR, Chuang JL, Cox RP, Fisher CW, Star RA, Chuang DT. Maple syrup urine disease in Mennonites. Evidence that the Y393N mutation in E1 alpha impedes assembly of the E1 component of branched-chain alpha-keto acid dehydrogenase complex. J Clin Invest. 1991 Sep;88(3):1034-7. PMID:1885764 doi:http://dx.doi.org/10.1172/JCI115363
- ↑ Nobukuni Y, Mitsubuchi H, Hayashida Y, Ohta K, Indo Y, Ichiba Y, Endo F, Matsuda I. Heterogeneity of mutations in maple syrup urine disease (MSUD): screening and identification of affected E1 alpha and E1 beta subunits of the branched-chain alpha-keto-acid dehydrogenase multienzyme complex. Biochim Biophys Acta. 1993 Nov 25;1225(1):64-70. PMID:8161368
- ↑ Chuang JL, Davie JR, Chinsky JM, Wynn RM, Cox RP, Chuang DT. Molecular and biochemical basis of intermediate maple syrup urine disease. Occurrence of homozygous G245R and F364C mutations at the E1 alpha locus of Hispanic-Mexican patients. J Clin Invest. 1995 Mar;95(3):954-63. PMID:7883996 doi:http://dx.doi.org/10.1172/JCI117804
- ↑ Machius M, Wynn RM, Chuang JL, Li J, Kluger R, Yu D, Tomchick DR, Brautigam CA, Chuang DT. A versatile conformational switch regulates reactivity in human branched-chain alpha-ketoacid dehydrogenase. Structure. 2006 Feb;14(2):287-98. PMID:16472748 doi:10.1016/j.str.2005.10.009
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