Molecular insights into prolyl and lysyl hydroxylation of fibrillar collagens in health and disease

Abstract

Collagen is a macromolecule that has versatile roles in physiology, ranging from structural support to mediating cell signaling. Formation of mature collagen fibrils out of procollagen α-chains requires a variety of enzymes and chaperones in a complex process spanning both intracellular and extracellular post-translational modifications. These processes include modifications of amino acids, folding of procollagen α-chains into a triple-helical configuration and subsequent stabilization, facilitation of transportation out of the cell, cleavage of propeptides, aggregation, cross-link formation, and finally the formation of mature fibrils. Disruption of any of the proteins involved in these biosynthesis steps potentially result in a variety of connective tissue diseases because of a destabilized extracellular matrix. In this review, we give a revised overview of the enzymes and chaperones currently known to be relevant to the conversion of lysine and proline into hydroxyproline and hydroxylysine, respectively, and the O-glycosylation of hydroxylysine and give insights into the consequences when these steps are disrupted.

The lysyl oxidase like 2/3 enzymatic inhibitor, PXS‐5153A, reduces crosslinks and ameliorates fibrosis

“…The mechanism by which collagen crosslinks are formed is based on the reactions of allysine or hydroxyallysines present on collagen side‐chains with other aldehydes or with unmodified lysine or hydroxylysine residues, resulting in the formation of crosslinks . The availability of hydroxyallysine is the direct result of lysine hydroxylation, through a process driven by lysyl hydroxylases . In bone, tendon, ligaments and cartilage, the collagen is crosslinked mainly via the hydroxyallysine route, whereas in skin the crosslinks are derived from the allysine route .…”

The Chemistry of Protein Oxidation in Food

“…[94] Proline and lysine are hydroxylated by dioxygenases,which require iron, ascorbate,and molecular oxygen as co-substrates.3 -a nd 4-hydroxyproline as well as 5-hydroxylysine stabilize the collagen molecule. [95] Enzymatic reactions can either induce the formation of reactive species in food or directly lead to the oxidation of free or protein-bound amino acids in order to modify their functional properties.I nh oney,g lucose oxidase generates H 2 O 2 as am ajor antibacterial factor (inhibin). [96] Lipoxygenase,e.g., from soy flour,may lead to bleaching of wheat flour and doughs by lipid peroxidation and carotenoid degradation.…”

“…[143] This means,t hat the protein can be carbonylated but, at the same time,n ot oxidized ( Figure 2). Interestingly,n one of the proteinogenic amino acids bears ac arbonyl group,a nd thus,c arbonylated amino acids are not intrinsic constituents of native proteins, which points to avoidance of this highly reactive functional group in biosynthetic pathways.O nly in few cases are aldehyde groups synthesized during post-translational protein processing, e.g.,the oxidation of (hydroxy)lysine to (hydroxy)allysine by lysyl oxidases [95] or the formation of formylglycine from cysteine in sulfatases. [144]…”

Die Chemie der Proteinoxidation in Lebensmitteln

“…3-und 4-Hydroxyprolin sowie 5-Hydroxylysin stabilisieren das Collagenmolekül. [95] Enzymatische Reaktionen kçnnen entweder die Bildung reaktiver Spezies induzieren oder direkt zur Oxidation freier oder proteingebundener Aminosäuren führen und so ihre funktionellen Eigenschaften verändern. In Honig bildet die Glucose-Oxidase H 2 O 2 als wesentlichen antibakteriellen Faktor ("Inhibin").…”

“…Nur in einzelnen Fällen werden Aldehydgruppen während der posttranslationalen Proteinprozessierung eingefügt, z. B. bei der Oxidation von (Hydroxy)lysin zum (Hydroxy)allysin durch Lysyloxidasen [95] oder bei der Bildung von Formylglycin aus Cystein in Sulfatasen. [144] 3.3.…”