C10orf65 Inhibitors

4-Hydroxy-2-oxoglutarate aldolase 1, encoded by the gene HOGA1, is an intracellular metabolic enzyme that plays a crucial role in the hydroxyproline degradation pathway. This pathway is part of the broader amino acid catabolism processes within the mitochondrion, where 4-hydroxy-2-oxoglutarate aldolase 1 catalyzes the cleavage of 4-hydroxy-2-oxoglutarate (also known as 4-hydroxy-2-ketoglutarate) to pyruvate and glyoxylate.The enzyme's function is particularly important in the context of collagen turnover. Hydroxyproline, found in the breakdown of collagen, is metabolized through a series of reactions, with 4-hydroxy-2-oxoglutarate aldolase 1 facilitating one of the final steps. The reaction it catalyzes is an aldol cleavage, which is a type of carbon-carbon bond breakage that is common in metabolic pathways involving carbohydrates and related compounds.

Mutations in the HOGA1 gene can lead to a rare autosomal recessive metabolic disorder known as primary hyperoxaluria type 3 (PH3). Individuals with this disorder have elevated levels of oxalate and glycolate in the urine, which can lead to kidney stones and nephrocalcinosis. This is due to the accumulation of upstream metabolites, such as 4-hydroxy-2-oxoglutarate, resulting from insufficient activity of the enzyme. As an enzyme with a specialized role in amino acid degradation, 4-hydroxy-2-oxoglutarate aldolase 1 is an essential component for maintaining amino acid and energy homeostasis. Its activity reflects the body's ability to effectively manage and recycle the components of collagen, which is the most abundant protein in mammals, providing structural support to tissues and organs.Research into the function and structure of 4-hydroxy-2-oxoglutarate aldolase 1 continues to provide valuable insights into not only metabolic pathways but also into approaches for managing conditions like primary hyperoxaluria.