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C -Mannosylation is a post-translational modification of proteins in the endoplasmic reticulum. Monomeric α-mannose is attached to specific Trp residues at the first Trp in the Trp-x-x-Trp/Cys (W-x-x-W/C) motif of substrate proteins, by the action of C -mannosyltransferases, DPY19 -related gene products. The acceptor substrate proteins are included in the thrombospondin type I repeat (TSR) superfamily, cytokine receptor type I family, and others. Previous studies demonstrated that C -mannosylation plays critical roles in the folding, sorting, and/or secretion of substrate proteins. A C -mannosylation-defective gene mutation was identified in humans as the disease-associated variant affecting a C -mannosylation motif of W-x-x-W of ADAMTSL1, which suggests the involvement of defects in protein C -mannosylation in human diseases such as developmental glaucoma, myopia, and/or retinal defects. On the other hand, monomeric C -mannosyl Trp ( C -Man-Trp), a deduced degradation product of C -mannosylated proteins, occurs in cells and extracellular fluids. Several studies showed that the level of C -Man-Trp is upregulated in blood of patients with renal dysfunction, suggesting that the metabolism of C -Man-Trp may be involved in human kidney diseases. Together, protein C -mannosylation is considered to play important roles in the biosynthesis and functions of substrate proteins, and the altered regulation of protein C -manosylation may be involved in the pathophysiology of human diseases. In this review, we consider the biochemical and biomedical knowledge of protein C -mannosylation and C -Man-Trp, and introduce recent studies concerning their significance in biology and medicine.

Protein C-Mannosylation and C-Mannosyl Tryptophan in Chemical Biology and Medicine