Abstract
One of the proposed mechanisms of homocysteine toxicity in human is the modification of proteins by the metabolite of Hcy, homocysteine thilolactone (HTL). Incubation of proteins with HTL has earlier been shown to form covalent adducts with ε-amino group of lysine residues of protein (called N-homocysteinylation). It has been believed that protein N-homocysteinylation is the pathological hallmark of cardiovascular and neurodegenerative disorders as homocysteinylation induces structural and functional alterations in proteins. In the present study, reactivity of HTL towards proteins with different physico-chemical properties and hence their structural and functional alterations were studied using different spectroscopic approaches. We found that N-homocysteinylation has opposite consequences on acidic and basic proteins suggesting that pI of the protein determines the extent of homocysteinylation, and the structural and functional consequences due to homocysteinylation. Mechanistically, pI of protein determines the extent of N-homocysteinylation and the associated structural and functional alterations. The study suggests the role of HTL primarily targeting acidic proteins in eliciting its toxicity that could yield mechanistic insights for the associated neurodegeneration.
Highlights
Hyperhomocysteinemia/homocystinuria is a genetic disorder of methionine metabolism caused due to elevated level of plasma homocysteine (Hcy)
Urinary excretion of homocysteine thilolactone (HTL) in the kidneys [3, 18] and serum homocysteine-thiolactonase associated with high density lipoprotein which is known to hydrolyse HTL [19], form the extracellular mode of HTL clearance from the body, while bleomycin hydrolase (BHL) is the major intracellular HTL-hydrolysing enzyme which protects the cells against intracellular HTL [20]
This figure indicates that HTL-induced modification has different structural consequences on a-LA relative to lysozyme and RNase-A, in terms of secondary and tertiary structures
Summary
Hyperhomocysteinemia/homocystinuria is a genetic disorder of methionine metabolism caused due to elevated level of plasma homocysteine (Hcy). The total concentrations of plasma Hcy may range from 15–20 mM (mild forms) up to 500 mM (severe forms), compared with 5–10 mM under normal conditions [6, 7, 8, 9, 10, 11]. This elevated Hcy levels are associated with increased incidences of cardiovascular diseases, including atherosclerosis and thrombosis [12, 13], pregnancy disorders [14] and with various neurodegenerative pathologies such as dementia, Parkinson’s and Alzheimer’s diseases [15, 16, 17]. Under severe hyperhomocysteinemic conditions, the effectiveness of these mechanisms in protecting cells against HTL toxicity are still not yet investigated and properly understood
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