Abstrakt

Metylacja argininy uznawana jest za jedną z najtrwalszych i najczęściej występujących modyfikacji potranslacyjnych. Reakcja przeniesienia grupy metylowej z S-adenyzolometioniny na aminową resztę argininy katalizowana jest przez metylotransferazy argininy (PRMT). W organizmie człowieka znanych jest dziewięć enzymów z rodziny PRMT, nazwanych zgodnie z kolejnością odkrycia PRMT1-PRMT9. Ze względu na produkt katalizowanej reakcji metylotransferazy argininy podzielono na trzy klasy: I, II, III. Produktami ich aktywności są odpowiednio: asymetryczna dimetyloarginina (ADMA), symetryczna dimetyloarginina (SDMA) oraz monometyloarginina (MMA). Powstałe modyfikacje w istotny sposób wpływają na strukturę chromatyny, dzięki czemu mogą pełnić funkcję koaktywatorów i supresorów transkrypcji. Metylacja argininy pełni wiele krytycznych funkcji, niezbędnych do prawidłowego funkcjonowania organizmu. Uczestniczy m.in. w kontroli transdukcji sygnału, splicingu mRNA oraz reguluje podstawowe procesy komórkowe, takie jak: proliferacja, różnicowanie, migracja i apoptoza. Coraz więcej dowodów wskazuje, że dysregulacja poziomu PRMT może powadzić do transformacji nowotworowej. Związek między podwyższonym poziomem PRMT a chorobą nowotworową udowodniono m.in. w raku: piersi, jajnika, płuc i jelita grubego. Aktywność metylotransferaz argininy może być regulowana za pomocą małocząsteczkowych inhibitorów PRMT. Obecnie trzy substancje hamujące aktywność PRMT znajdują się w fazie badań klinicznych i wykazują działanie przeciwnowotworowe wobec nowotworów hematologicznych. Przypuszcza się, że zastosowanie swoistych inhibitorów PRMT może się okazać nowym, skutecznym i bezpiecznym sposobem zwalczania chorób onkologicznych.

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