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Review
. 2022 Jan 17;23(2):1005.
doi: 10.3390/ijms23021005.

Catabolism of Hydroxyproline in Vertebrates: Physiology, Evolution, Genetic Diseases and New siRNA Approach for Treatment

Ruth Belostotsky  1 , Yaacov Frishberg  1
Affiliations
Review

Catabolism of Hydroxyproline in Vertebrates: Physiology, Evolution, Genetic Diseases and New siRNA Approach for Treatment

Ruth Belostotsky et al. Int J Mol Sci. .

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.

Keywords: HIF-1α; collagen post-translational modification; glyoxylate; hydroxyproline; oxalate; primary hyperoxaluria; prolyl hydroxylase; protein compartmentalization; small interference RNA.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of proline hydroxylation (A), catabolism of 3-hydroxyproline (B), and 4-hydroxyproline (C). Gene designation in italic; protein designation (if different) in regular. PH1, PH2, PH3-types of primary hyperoxaluria.
Figure 2
Figure 2
The catabolic pathway of 4-hydroxyproline in various vertebrate species.
See this image and copyright information in PMC

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