Reacciones de N-homocisteinilación asociadas a hiperhomocisteinemia / N-homocysteinylation reactions related to hyperhomocysteinemia / Reações de N-homocisteinilação associadas a hiper-homocisteinemia

Numerosas evidencias clínicas avalan la asociación entre concentración plasmática elevada de homocisteína (hiperhomocisteinemia) y las enfermedades vasculares oclusivas, tales como la aterosclerosis y la trombosis. La homocisteína reducida (Hcy) y su éster cíclico homocisteína-tiolactona (HTL) serían los principales responsables de los efectos nocivos asociados a la hiperhomocisteinemia. Tanto la Hcy como la HTL pueden interactuar espontáneamente con proteínas, a través de reacciones de S y N-homocisteinilación, respectivamente. Ambos procesos provocan alteraciones proteicas post-traduccionales, e inducen cambios estructurales y funcionales a nivel molecular. En los últimos años ha cobrado interés el conocimiento acerca de la HTL y las consecuencias de concentraciones elevadas de este metabolito sobre la salud humana. En las reacciones de N-homocisteinilación, el grupo carbonilo de la HTL se une al grupo ε-amino de los residuos lisina de las proteínas, con lo que se generan grupos sulfhidrilo libres, susceptibles de participar en reacciones redox. Las proteínas N-homocisteiniladas pueden sufrir plegamiento incorrecto de la molécula y daño oxidativo, y en consecuencia se inducen efectos citotóxicos e inmunogénicos. Se ha establecido que la conversión metabólica de la Hcy en HTL y la N-homocisteinilación de proteínas es uno de los mecanismos involucrados en el desarrollo de patologías asociadas con la hiperhomocisteinemia, tales como las enfermedades cardiovasculares y neurodegenerativas.

Increased plasma homocysteine levels (hyperhomocysteinemia) are associated with occlusive vascular diseases, such as atherosclerosis and thrombosis. Reduced homocysteine (Hcy) and its cyclic ester, homocysteine thiolactone (HTL) would be involved in the detrimental effects associated to hyperhomocysteinemia. These two species, Hcy and HTL can spontaneously react with proteins, through S and N-homocysteinylation process, respectively. Both reactions produce post-translational protein changes, impairing structural and functional features. In recent years, interest has been developed in HTL and its effects on human health. N-homocysteinylation is the reaction between the carboxyl group of HTL and ε-amino group of lysine residues, rendering free sulfhydryl groups able to participate in redox reactions. N-homocysteinylated proteins are prone to misfolding and oxidative damage, inducing cytotoxic and immunogenic effects. Metabolic conversion of Hcy to HTL as well as protein N-homocysteinylation is one of the mechanisms underlying the development of pathologies associated to hyperhomocysteinemia, such as cardiovascular and neurodegenerative diseases.

Numerosas evidências clínicas garantem a associação entre concentração plasmática elevada de homocisteína (hiper-homocisteinemia) e as doenças vasculares oclusivas, tais como a aterosclerose e a trombose. A homocisteína reduzida (Hcy) e seu éster cíclico homocisteína tiolactona (HTL) seriam os principais responsáveis pelos efeitos nocivos associados à hiper-homocisteinemia. Tanto a Hcy quanto a HTL podem interagir espontaneamente com proteínas, através de reações de S e N-homocisteinilação, respectivamente. Ambos os processos provocam alterações proteicas pós-traducionais, induzindo alterações estruturais e funcionais em nível molecular. Nos últimos anos, cobrou interesse o conhecimento acerca da HTL e as consequências de concentrações elevadas deste metabólito sobre a saúde humana. Nas reações de N-homocisteinilação, o grupo carbonila da HTL se une ao grupo ε-amino dos resíduos lisina das proteínas, gerando grupos sulfidrila livres, suscetíveis de participar em reações redox. As proteínas N-homocisteiniladas podem sofrer dobramento incorreto da molécula e dano oxidativo, induzindo efeitos citotóxicos e imunogênicos. Estabeleceu-se que a conversão metabólica da Hcy em HTL e a N-homocisteinilação de proteínas é um dos mecanismos envolvidos no desenvolvimento de patologias associadas com a hiper-homocisteinemia, tais como as doenças cardiovasculares e neurodegenerativas.

The C677T thermolabile variant of methylene tetrahydrofolate reductase on homocysteine, folate and vitamin B12 in a hemodialysis center

Homocysteine is a risk factor for cardiovascular disease. Mutations in a key enzyme in homocysteine metabolism, methylenetetrahydrofolate reductase, may contribute to hyperhomocysteinemia and alter folate and cobalamin levels. After starting hemodialysis, 10 mg oral folate daily and 500 micrograms intravenous methylcobalamin once weekly were prescribed to 27 hemodialysis patients (time on hemodialysis > or = 12 months) and two groups were defined: Group A normal; Group B heterozygous. Initial, third and twelfth month measurements of homocysteine, serum folate and vitamin B12 levels were collected and analyzed. Heterozygous state of methylenetetrahydrofolate reductase prevalence was 48

. Hyperhomocysteinemia was present in both groups. Cobalamin final levels were significantly lower in Group B compared to Group A. Homocysteine, serum folate and cobalamin levels at third and twelfth month were significantly different from baseline levels but non-different between them in both groups. In Group B, vitamin B12 at third month was significantly higher than initial, but final measurements were not different from baseline determinations. In conclusion, the heterozygous prevalence of the enzyme in hemodialysis patients is similar to that reported in the general population; hyperhomocysteinemia is frequent in hemodialysis patients and final levels in heterozygous patients are significantly higher than in normal patients. Cobalamin levels are lower in the heterozygous group. After one year of treatment, homocysteine tends to increase, suggesting a secondary resistance phenomenon to vitamin supplementation in heterozygous patients.