Abstract
Hydroxyproline is one of the most prevalent amino acids in animal proteins. It is not a genetically encoded amino acid, but, rather, it is produced by the post-translational modification of proline in collagen, and a few other proteins, by prolyl hydroxylase enzymes. Although this post-translational modification occurs in a limited number of proteins, its biological significance cannot be overestimated. Considering that hydroxyproline cannot be re-incorporated into pro-collagen during translation, it should be catabolized following protein degradation. A cascade of reactions leads to production of two deleterious intermediates: glyoxylate and hydrogen peroxide, which need to be immediately converted. As a result, the enzymes involved in hydroxyproline catabolism are located in specific compartments: mitochondria and peroxisomes. The particular distribution of catabolic enzymes in these compartments, in different species, depends on their dietary habits. Disturbances in hydroxyproline catabolism, due to genetic aberrations, may lead to a severe disease (primary hyperoxaluria), which often impairs kidney function. The basis of this condition is accumulation of glyoxylate and its conversion to oxalate. Since calcium oxalate is insoluble, children with this rare inherited disorder suffer from progressive kidney damage. This condition has been nearly incurable until recently, as significant advances in substrate reduction therapy using small interference RNA led to a breakthrough in primary hyperoxaluria type 1 treatment.
Highlights
Depending on which substrate is the main precursor of glyoxylate, alanine: glyoxylate aminotransferase (AGT), an enzyme that catalyzes the final step of 4-Hyp catabolism—the conversion of glyoxylate to glycine has distinct organelle distribution in species with diverse dietary habits [10]
Collagens are deposited in the extracellular matrix, and they interact with cells through several families of receptors, mainly through integrins, dimeric discoidin receptors (DDR), and glycoprotein VI
Primary hyperoxaluria results from excessive Ox production due to the concomitant activity of lactate dehydrogenase (LDH) (Figures 1C and 2)
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Depending on which substrate is the main precursor of glyoxylate, alanine: glyoxylate aminotransferase (AGT), an enzyme that catalyzes the final step of 4-Hyp catabolism—the conversion of glyoxylate to glycine has distinct organelle distribution in species with diverse dietary habits [10]. It is localized in the mitochondria of carnivores, where the main contribution comes from dietary collagen degradation and the formation of Hyp. In herbivores, where the major source of glyoxylate comes from dietary glycolate, it is peroxisomal, while in omnivores it has dual localization. SRT based on small molecule inhibitors and additional targets for RNAi, which can expand application to other forms of PH, are currently under development [13]
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