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1.
Amino Acids ; 46(3): 621-31, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24129980

RESUMO

Histamine plays highlighted roles in the development of many common, emergent and rare diseases. In mammals, histamine is formed by decarboxylation of L-histidine, which is catalyzed by pyridoxal-5'-phosphate (PLP) dependent histidine decarboxylase (HDC, EC 4.1.1.22). The limited availability and stability of the protein have delayed the characterization of its structure-function relationships. Our previous knowledge on mammalian HDC, derived from both in silico and experimental approaches, indicates that an effective competitive inhibitor should be capable to form an "external aldimine-like structure" and have an imidazole group, or its proper mimetic, which provides additional affinity of PLP-inhibitor adduct to the HDC active center. This is confirmed using HEK-293 cells transfected to express human HDC and the aminooxy analog of histidine, 4(5)-aminooxymethylimidazole (O-IMHA, IC50 ≈ 2 × 10(-7) M) capable to form a PLP-inhibitor complex (oxime) in the enzyme active center. Taking advantage of the availability of the human HDC X-ray structure, we have also determined the potential interactions that could stabilize this oxime in the active site of mammalian HDC.


Assuntos
Inibidores Enzimáticos/farmacologia , Histidina Descarboxilase/antagonistas & inibidores , Hidroxilaminas/farmacologia , Imidazóis/farmacologia , Inibidores Enzimáticos/química , Histidina Descarboxilase/metabolismo , Humanos , Hidroxilaminas/química , Imidazóis/química , Simulação de Dinâmica Molecular , Estrutura Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
2.
Clin Genet ; 78(5): 441-8, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20236116

RESUMO

Methylenetetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism. Disturbed function of the enzyme results in hyperhomocysteinemia and causes severe vascular and neurological disorders and developmental delay. Five patients suspected of having non-classical homocystinuria due to MTHFR deficiency were examined with respect to their symptoms, MTHFR enzyme activity and genotypes of the MTHFR gene. All patients presented symptoms of severe central nervous system disease. Two patients died, at the ages of 15 months and 14 years. One patient is currently 32 years old, and is being treated with betaine and folinic acid. The other two patients, with an early diagnosis and a severe course of the disease, are currently improving under treatment. MTHFR enzyme activity in the fibroblasts of four of the patients was practically undetectable. We found four novel mutations, three of which were missense changes c.664G> T (p.V218L), c.1316T> C (p.F435S) and c.1733T> G (p.V574G), and the fourth was the 1-bp deletion c.1780delC (p.L590CfsX72). We also found the previously reported nonsense mutation c.1420G> T (p.E470X). All the patients were homozygous. Molecular modelling of the double mutant allele (p.V218L; p.A222V) revealed that affinity for FAD was not affected in this mutant. For the p.E470X mutation, the evidence pointed to nonsense-mediated mRNA decay. In general, genotype-phenotype analysis predicts milder outcomes for patients with missense changes than for those in which mutations led to severe alterations of the MTHFR protein.


Assuntos
Homocistinúria/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Adolescente , Adulto , Betaína/uso terapêutico , Pré-Escolar , Evolução Fatal , Feminino , Homocistinúria/tratamento farmacológico , Homocistinúria/enzimologia , Humanos , Lactente , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Modelos Moleculares , Tetra-Hidrofolatos/uso terapêutico , Termodinâmica
3.
Proteins ; 78(1): 154-61, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19790266

RESUMO

There is some evidence linking the substrate entrance in the active site of mammalian histidine decarboxylase and an increased stability against proteolytic degradation. In this work, we study the basis of this relationship by means of protein structure network analysis and molecular dynamics simulations. We find that the substrate binding to the active site influences the conformation of a flexible region sensible to proteolytic degradation and observe how formation of the Michaelis-Menten complex increases stability in the conformation of this region.


Assuntos
Histidina Descarboxilase/química , Histidina Descarboxilase/metabolismo , Animais , Mamíferos/metabolismo , Simulação de Dinâmica Molecular , Movimento (Física) , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Estabilidade Proteica , Especificidade por Substrato
4.
Br J Pharmacol ; 157(1): 4-13, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19413567

RESUMO

For a long time the structural and molecular features of mammalian histidine decarboxylase (EC 4.1.1.22), the enzyme that produces histamine, have evaded characterization. We overcome the experimental problems for the study of this enzyme by using a computer-based modelling and simulation approach, and have now the conditions to use histidine decarboxylase as a target in histamine pharmacology. In this review, we present the recent (last 5 years) advances in the structure-function relationship of histidine decarboxylase and the strategy for the discovery of new drugs.


Assuntos
Simulação por Computador , Inibidores Enzimáticos/química , Histidina Descarboxilase/química , Modelos Moleculares , Animais , Sítios de Ligação , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Histidina Descarboxilase/antagonistas & inibidores , Histidina Descarboxilase/fisiologia , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade , Termodinâmica
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