The hexosamine biosynthetic pathway (HBP) results in the production of
UDP-N-acetylglucosamine (UDP-GlcNAc) and other nucleotide hexosamines.
UDP-GlcNAc, the major product, is the unique donor for the O-linkage of a
single N-acetylglucosamine molecule (O-GlcNAc) to many cytoplasmic and nuclear
proteins. Upon entering the cell, glucose is rapidly phosphorylated to
glucose-6-phosphate (G6P), which can be oxidized via glycolysis or the pentose
phosphate shunt or stored as glycogen. In glycoly
sis, G6P is isomerized to fructose-6-phosphate (F6P) before the pathway proceeds. Approximately 2-5% of F6P, and for that matter glucose, is diverted to HBP. Gfpt1 (known as Gfat) catalyzes the formation of glucosamine-6-phosphate with glutamine as an amine donor and F6P as an acceptor substrate in the first
and rate-limiting step of the pathway. Subsequently, the addition of an acetyl group
yields N-acetyl glucosamine-6-phosphate, which is rapidly modified to
UDP-GlcNAc. The utilization of glucosamine and of acetyl in the first two steps
potentially links amino acid and fatty acid metabolism with HBP. The
reversible modification of proteins by the addition and removal of GlcNAc,
analogous to addition and removal of phosphate, also has a complex interplay
with the O-phosphate modification. Sites that are targets of O-GlcNAcylation
are at or near sites of O-phosphorylation. The cycling of GlcNAc is carried out
by two enzymes: Ogt that catalyzes the O-linkage to serine and threonine
residues and Mgea5 (known as Oga) that removes the hexosamine moiety. The
cycling of GlcNAc and the regulation of the two enzymes are subjects of intense
research as the many targets of GlcNAcylation represent almost every
functional class, including proteins involved in insulin synthesis and
signaling, and in the expression of gluconeogenic enzymes. Some 600 targets have
been identified, but little is known about the functional significance of
their modification. Due to the broad functionality of target proteins, the
hexosamine pathway is also referred to as the "hexosamine signaling pathway". The
end product, UDP-GlcNAc, is a potent inhibitor of Gfat and also modulates the
affinity of Ogt for individual substrates. Ogt contains several tetratricopeptide
repeats (TPR) at the N-terminus that mediate protein-protein interactions. Studies
have shown that perturbations of the HBP associate with insulin resistance, glucose
toxicity and other complications of diabetes, but a direct role and/or
mechanisms remain to be established.To see the
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