Dolichol phosphate mannose synthase (
DPMS) is an inverting GT-A-folded
enzyme and classified as GT2 by CAZy.
DPMS sequence carries a
metal-binding DXD motif, a PKA motif, and a variable number of hydrophobic domains. Human and bovine
DPMS possess a single transmembrane domain, whereas that from S. cerevisiae and A. thaliana carry multiple transmembrane domains and are superimposable. The catalytic activity of
DPMS is documented in all spheres of life, and the 32kDa
protein is uniquely regulated by
protein phosphorylation. Intracellular activation of
DPMS by cAMP signaling is truly due to the activation of the
enzyme and not due to increased Dol-P level. The sequence of
DPMS in some species also carries a
protein N-glycosylation motif (Asn-X-Ser/Thr). Apart from participating in N-
glycan biosynthesis,
DPMS is essential for the synthesis of GPI anchor as well as for O- and C-mannosylation of
proteins. Because of the dynamic nature,
DPMS actively participates in cellular proliferation enhancing angiogenesis and
breast tumor progression. In fact, overexpression of
DPMS in capillary endothelial cells supports increased N-glycosylation, cellular proliferation, and enhanced chemotactic activity. These are expected to be completely absent in
congenital disorders of glycosylation (CDGs) due to the silence of
DPMS catalytic activity.
DPMS has also been found to be involved in the cross talk with N-acetylglucosaminyl 1-phosphate
transferase (GPT). Inhibition of GPT with
tunicamycin downregulates the
DPMS catalytic activity quantitatively. The result is impairment of surface N-
glycan expression, inhibition of angiogenesis, proliferation of human
breast cancer cells, and induction of apoptosis. Interestingly, nano-formulated
tunicamycin is three times more potent in inhibiting the cell cycle progression than the native
tunicamycin and is supported by downregulation of the ratio of phospho-p53 to total-p53 as well as phospho-Rb to total Rb.
DPMS expression is also reduced significantly. However, nano-formulated
tunicamycin does not induce apoptosis. We, therefore, conclude that
DPMS could become a novel target for developing glycotherapy treating
breast tumor in the clinic.