JMJD8 Activators

Chemical activators of JMJD8 can directly enhance the enzymatic function of this histone demethylase. 2-Oxoglutarate and its alternative form, α-Ketoglutarate, are critical co-substrates for JMJD8, providing the necessary chemical environment for the demethylation of histones. Their presence in sufficient quantities ensures that JMJD8 can carry out its enzymatic duties effectively. Iron(II) sulfate is another component essential for JMJD8's activity, as it supplies Fe2+, which is required at the active site of JMJD8 for its histone demethylase function. Without the presence of Fe2+, JMJD8 cannot catalyze the demethylation reaction, hence the importance of iron(II) sulfate.

Ascorbic acid and its variant, L-ascorbic acid, also known as Vitamin C, maintain the iron in its reduced Fe2+ state, which is a prerequisite for the catalysis performed by JMJD8. This reduction is vital for the prevention of Fe3+ accumulation, which would otherwise inhibit JMJD8's activity. The presence of NOG (N-Oxalylglycine) can indirectly enhance JMJD8 activity by reducing competition from other 2-oxoglutarate-dependent dioxygenases, thus ensuring that JMJD8 has access to adequate levels of 2-oxoglutarate. Moreover, the involvement of metabolic intermediates such as succinic acid, fumaric acid, citric acid, and malic acid in the tricarboxylic acid (TCA) cycle can influence the cellular concentrations of 2-oxoglutarate, indirectly supporting the catalytic activity of JMJD8. Pyridoxal phosphate, a coenzyme for a variety of enzymatic reactions, might support metabolic pathways that supply substrates or cofactors necessary for JMJD8 function. These chemicals, by ensuring the availability of cofactors and substrates, activate JMJD8, allowing it to perform its role in modifying histones and, consequently, regulating gene expression.