Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase

DOPA decarboxylase (DDC) is responsible for the synthesis of the key neurotransmitters dopamine and serotonin via decarboxylation of l-3,4-dihydroxyphenylalanine (l-DOPA) and l-5-hydroxytryptophan, respectively. DDC has been implicated in a number of clinic disorders, including Parkinson's disease and hypertension. Peripheral inhibitors of DDC are currently used to treat these diseases. We present the crystal structures of ligand-free DDC and its complex with the anti-Parkinson drug carbiDOPA. The inhibitor is bound to the enzyme by forming a hydrazone linkage with the cofactor, and its catechol ring is deeply buried in the active site cleft. The structures provide the molecular basis for the development of new inhibitors of DDC with better pharmacological characteristics.

[1]  W. Vogel,et al.  Effects of L-DOPA/carbidopa administration on the levels of L-DOPA, other amino acids and related compounds in the plasma, brain and heart of the rat. , 1997, Pharmacology.

[2]  G. Eichele,et al.  Three-dimensional structure of a pyridoxal-phosphate-dependent enzyme, mitochondrial aspartate aminotransferase. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[3]  U. Kang,et al.  Potential of gene therapy for Parkinson's disease: neurobiologic issues and new developments in gene transfer methodologies. , 1998, Movement disorders : official journal of the Movement Disorder Society.

[4]  Z. Otwinowski,et al.  [20] Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[5]  M Karplus,et al.  Anatomy of a conformational change: hinged "lid" motion of the triosephosphate isomerase loop. , 1990, Science.

[6]  M. Hennig,et al.  Crystal structure of glutamate-1-semialdehyde aminomutase: an alpha2-dimeric vitamin B6-dependent enzyme with asymmetry in structure and active site reactivity. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[7]  M. Aminoff.  Treatment of Parkinson's disease. , 1994, The Western journal of medicine.

[8]  V. Malashkevich,et al.  Preliminary X-ray analysis of a new crystal form of recombinant pig kidney DOPA decarboxylase. , 1999, Acta crystallographica. Section D, Biological crystallography.

[9]  A. Okamoto,et al.  Aromatic L‐amino acid decarboxylase: Conformational change in the flexible region around arg334 is required during the transaldimination process , 1998, Protein science : a publication of the Protein Society.

[10]  V. Malashkevich,et al.  Crystallization and preliminary X-ray analysis of pig kidney DOPA decarboxylase. , 1992, Journal of molecular biology.

[11]  G. Schneider,et al.  The manifold of vitamin B6 dependent enzymes. , 2000, Structure.

[12]  T. Tanaka,et al.  Flexible loop that is novel catalytic machinery in a ligase. Atomic structure and function of the loopless glutathione synthetase. , 1994, Biochemistry.

[13]  Z. Otwinowski,et al.  Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[14]  D J Brooks,et al.  L‐Dihydroxyphenylalanine and its decarboxylase: New ideas on their neuroregulatory roles , 1995, Movement disorders : official journal of the Movement Disorder Society.

[15]  M. Hackert,et al.  Structural motifs for pyridoxal‐5′‐phosphate binding in decarboxylases: An analysis based on the crystal structure of the Lactobacillus 30a ornithine decarboxylase , 1995, Protein science : a publication of the Protein Society.

[16]  Y. Agid,et al.  Adverse reactions to levodopa: drug toxicity or progression of disease? , 1998, The Lancet.

[17]  M. Bertoldi,et al.  Reaction Specificity of Native and Nicked 3,4-Dihydroxyphenylalanine Decarboxylase* , 1999, The Journal of Biological Chemistry.

[18]  J. Bloch,et al.  Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. , 2000, Science.

[19]  H. Hayashi,et al.  An anomalous side reaction of the Lys303 mutant aromatic L-amino acid decarboxylase unravels the role of the residue in catalysis. , 1997, Journal of biochemistry.

[20]  M. Bertoldi,et al.  Mutation of cysteine 111 in Dopa decarboxylase leads to active site perturbation , 1997, Protein science : a publication of the Protein Society.

[21]  V S Lamzin,et al.  wARP: improvement and extension of crystallographic phases by weighted averaging of multiple-refined dummy atomic models. , 1997, Acta crystallographica. Section D, Biological crystallography.

[22]  V. Malashkevich,et al.  Crystal structures of dialkylglycine decarboxylase inhibitor complexes. , 1999, Journal of molecular biology.

[23]  F. C. Hartman,et al.  Mechanistic insights provided by deletion of a flexible loop at the active site of ribulose-1,5-bisphosphate carboxylase/oxygenase. , 1995, Biochemistry.

[24]  J. Thibault,et al.  Structure modelling and site‐directed mutagenesis of the rat aromatic L‐amino acid pyridoxal 5´‐phosphate‐dependent decarboxylase: A functional study , 1999, Proteins.

[25]  P. Burkhard,et al.  Three-dimensional structure of O-acetylserine sulfhydrylase from Salmonella typhimurium. , 1998, Journal of molecular biology.

[26]  P. Burkhard,et al.  Ligand binding induces a large conformational change in O-acetylserine sulfhydrylase from Salmonella typhimurium. , 1999, Journal of molecular biology.

[27]  G. Murshudov,et al.  Refinement of macromolecular structures by the maximum-likelihood method. , 1997, Acta crystallographica. Section D, Biological crystallography.

[28]  E A Merritt,et al.  Raster3D: photorealistic molecular graphics. , 1997, Methods in enzymology.

[29]  J. Fetrow.  Omega loops; nonregular secondary structures significant in protein function and stability , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  F. Bossa,et al.  The Roles of His-167 and His-275 in the Reaction Catalyzed by Glutamate Decarboxylase from Escherichia coli * , 1998, The Journal of Biological Chemistry.

[31]  L. Mucke,et al.  Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. , 2000, Science.

[32]  G. Eichele,et al.  Mechanism of action of aspartate aminotransferase proposed on the basis of its spatial structure. , 1984, Journal of molecular biology.

[33]  T. Clausen,et al.  Crystal structure of cystalysin from Treponema denticola: a pyridoxal 5′‐phosphate‐dependent protein acting as a haemolytic enzyme , 2000, The EMBO journal.

[34]  A. Fersht,et al.  Mutational and kinetic analysis of a mobile loop in tyrosyl-tRNA synthetase. , 1993, Biochemistry.

[35]  H. Dunathan.  Conformation and reaction specificity in pyridoxal phosphate enzymes. , 1966, Proceedings of the National Academy of Sciences of the United States of America.

[36]  P. Kraulis.  A program to produce both detailed and schematic plots of protein structures , 1991 .

[37]  J. Jansonius,et al.  Structure, evolution and action of vitamin B6-dependent enzymes. , 1998, Current opinion in structural biology.

[38]  R. John,et al.  Pyridoxal phosphate-dependent enzymes. , 1995, Biochimica et biophysica acta.

[39]  P. Christen,et al.  Evolutionary relationships among pyridoxal‐5′‐phosphate‐dependent enzymes , 1994 .

[40]  H. Hayashi,et al.  Functionally important residues of aromatic L-amino acid decarboxylase probed by sequence alignment and site-directed mutagenesis. , 1996, Journal of biochemistry.

[41]  S. Cowan,et al.  Dialkylglycine decarboxylase structure: bifunctional active site and alkali metal sites. , 1994, Science.

[42]  G. Bricogne,et al.  [27] Maximum-likelihood heavy-atom parameter refinement for multiple isomorphous replacement and multiwavelength anomalous diffraction methods. , 1997, Methods in enzymology.

[43]  R. Ghosh,et al.  Crystallographic structure of a PLP-dependent ornithine decarboxylase from Lactobacillus 30a to 3.0 A resolution. , 1995, Journal of molecular biology.

[44]  G. C. Wagner,et al.  L-DOPA exacerbates amphetamine-induced dopamine depletion. , 1998, Molecular and chemical neuropathology.

[45]  W. Bender,et al.  A Drosophila model of Parkinson's disease , 2000, Nature.

[46]  M. Bertoldi,et al.  Mutation of residues in the coenzyme binding pocket of Dopa decarboxylase. Effects on catalytic properties. , 2001, European journal of biochemistry.

[47]  J. Zou,et al.  Improved methods for building protein models in electron density maps and the location of errors in these models. , 1991, Acta crystallographica. Section A, Foundations of crystallography.

[48]  R J Read,et al.  Crystallography & NMR system: A new software suite for macromolecular structure determination. , 1998, Acta crystallographica. Section D, Biological crystallography.

[49]  Alexander McPherson,et al.  Preparation and analysis of protein crystals , 1982 .