DOPA decarboxylase

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==Mechanism==
==Mechanism==
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The mechanism of DDC catalyzed decarboxylation of L-Dopa to Dopamine has been well-studied due to the enzymes role in PD. Once again, the transimination step (conversion of internal to external aldimine) is common to all PLP-dependent enzymes. The subsequent orientation of the quinonoid intermediate allows for stereospecific decarboxylation of the substrate at the alpha carbon, as predicted by '''Dunathan's stereoelectronic hypothesis''' <ref name="dunathan">PMID:224217 </ref>, in which he proposed that the substrate binds PLP such that the bond made around the Cα that is going to be broken is aligned with the pi orbital system of the cofactor. This way, the developing p orbital is aligned for maximal overlap with the extended p system, lowering the energy of the transition state and increasing the rate of the reaction. As well, by controlling substrate orientation, the enzyme can distinguish between '''deprotonation''' and '''decarboxylation'''.
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The mechanism of DDC catalyzed decarboxylation of L-Dopa to Dopamine has been well-studied due to the enzymes role in PD. Once again, the transimination step (conversion of internal to external aldimine) is common to all PLP-dependent enzymes. The subsequent orientation of the quinonoid intermediate allows for stereospecific decarboxylation of the substrate at the alpha carbon, as predicted by '''Dunathan's stereoelectronic hypothesis''' <ref name="dunathan">PMID:224217 </ref>, in which he proposed that the substrate binds PLP such that the bond made around the Cα that is going to be broken is aligned with the pi orbital system of the cofactor.
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[[image:Dunathan.png|thumb|center|300px|'''Dunathan's Stereoeletronic Hypothesis, 1966''']] This way, the developing p orbital is aligned for maximal overlap with the extended p system, lowering the energy of the transition state and increasing the rate of the reaction. As well, by controlling substrate orientation, the enzyme can distinguish between '''deprotonation''' and '''decarboxylation'''.
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==Classification==
==Classification==
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Revision as of 16:39, 30 April 2012

Pig DOPA decarboxylase complex with inhibitor carbidopa, vitamin B6 phosphate and sulfate, 1js3

Drag the structure with the mouse to rotate

3D structures of DOPA decarboxylase

Update November 2011

3k40 – DDC – Drosophila melanogaster
1js3 – pDDC + inhibitor – pig
1js6 - pDDC
3rbf, 3rbl – hDDC – human
3rch – hDDC + vitamin B6 phosphate + pyridoxal phosphate

References


  1. 1.0 1.1 Schneider G, Kack H, Lindqvist Y. The manifold of vitamin B6 dependent enzymes. Structure. 2000 Jan 15;8(1):R1-6. PMID:10673430
  2. Miles EW. The tryptophan synthase alpha 2 beta 2 complex. Cleavage of a flexible loop in the alpha subunit alters allosteric properties. J Biol Chem. 1991 Jun 15;266(17):10715-8. PMID:1904055
  3. Burkhard P, Dominici P, Borri-Voltattorni C, Jansonius JN, Malashkevich VN. Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase. Nat Struct Biol. 2001 Nov;8(11):963-7. PMID:11685243 doi:http://dx.doi.org/10.1038/nsb1101-963
  4. Miles EW. The tryptophan synthase alpha 2 beta 2 complex. Cleavage of a flexible loop in the alpha subunit alters allosteric properties. J Biol Chem. 1991 Jun 15;266(17):10715-8. PMID:1904055
  5. Percudani R, Peracchi A. A genomic overview of pyridoxal-phosphate-dependent enzymes. EMBO Rep. 2003 Sep;4(9):850-4. PMID:12949584 doi:http://dx.doi.org/10.1038/sj.embor.embor914
  6. Maras B, Dominici P, Barra D, Bossa F, Voltattorni CB. Pig kidney 3,4-dihydroxyphenylalanine (dopa) decarboxylase. Primary structure and relationships to other amino acid decarboxylases. Eur J Biochem. 1991 Oct 15;201(2):385-91. PMID:1935935
  7. Aurora R, Rose GD. Helix capping. Protein Sci. 1998 Jan;7(1):21-38. PMID:9514257 doi:10.1002/pro.5560070103
  8. Jansonius JN. Structure, evolution and action of vitamin B6-dependent enzymes. Curr Opin Struct Biol. 1998 Dec;8(6):759-69. PMID:9914259
  9. 9.0 9.1 Ishii S, Mizuguchi H, Nishino J, Hayashi H, Kagamiyama H. Functionally important residues of aromatic L-amino acid decarboxylase probed by sequence alignment and site-directed mutagenesis. J Biochem. 1996 Aug;120(2):369-76. PMID:8889823
  10. Hiscott JB, Defendi V. Simian virus 40 gene A regulation of cellular DNA synthesis. I. In permissive cells. J Virol. 1979 May;30(2):590-9. PMID:224217
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