HypDB: A Functional Annotation Database of Proline Hydroxylation Proteome

Proline hydroxylation (Hyp) is an essential posttranslational modification for the regulation of cellular hypoxia response that is evolutionarily conserved. First discovered in 1902 [1], the modification adds a single oxygen atom to the 4R position on the proline pyrrolidine ring, which alters the chemical property of the amino acid through a strong electronegative effect. Such subtle changes contribute to the gauche effect and high trans:cis ratio observed in the hydroxylprolyl peptide bond, which are crucial for the stabilization of secondary structures in substrate proteins, such as collagen [2-5]. Although proline hydroxylation is an ancient modification, its functional significance in cell physiology and activity has been recognized only recently. As a key oxygen-sensing modification, proline hydroxylation is known to regulate oxygen-dependent degradation of hypoxia-inducible factor 1 alpha (HIF1A). A decrease in oxygen level leads to a decrease in the abundance of proline hydroxylation on its substrates. Such an effect contributes to the stabilization of HIF1A, and subsequent transcriptional activation of a plethora of over 100 genes in response to hypoxia, an elegant mechanism recognized by the 2016 Lasker Award and 2019 Nobel Prize [6-13].

As an irreversible modification, proline hydroxylation is catalyzed by evolutionarily-conserved prolyl-hydoxylases (PH) (EC 1.14.11.2), including prolyl 4-hydroxylase (P4H) and Prolyl Hydroxylase Domain (PHD) proteins. The catalysis by PHs depends on the availabilities of oxygen, Fe2+ and alpha-ketoglutarate (2-OG) in the cells [14-16]. Therefore, these regulatory enzymes of proline hydroxylation pathways are critical sensors of the cellular metabolic states.


References
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