Direct utilization of mannose for mammalian glycoprotein biosynthesis

Direct utilization of mannose for glycoprotein biosynthesis has not beenstudied because cellular mannose is assumed to be derived entirely fromglucose. However, animal sera contain sufficient mannose to force uptakethrough glucose-tolerant, mannose-specific transporters. Underphysiological conditions this transport system provides 75% of the mannosefor protein glycosylation in human hepatoma cells despite a 50- to 100-foldhigher concentration of glucose. This suggests that direct use of mannoseis more important than conversion from glucose. Consistent with thisfinding the liver is low in phosphomannose isomerase activity(fructose-6-P<->mannose-6-P), the key enzyme for supplyingglucose-derived mannose to the N-glycosylation pathway. [2- 3H] Mannose israpidly absorbed from the intestine of anesthetized rats and cleared fromthe blood with a t1/2of 30 min. After a 30 min lag, label is incorporatedinto plasma glycoproteins, and into glycoproteins of all organs during thefirst hour. Most (87%) of the initial incorporation occurs in the liver,but this decreases as radiolabeled plasma glycoproteins increase.Radiolabel in glycoproteins also increases 2- to 6-fold in other organsbetween 1-8 h, especially in lung, skeletal muscle, and heart. These organsmay take up hepatic- derived radiolabeled plasma glycoproteins.Significantly, the brain, which is not exposed to plasma glycoproteins,shows essentially no increase in radiolabel. These results suggest thatmammals use mannose transporters to deliver mannose from blood to the liverand other organs for glycoprotein biosynthesis. Additionally, contrary toexpectations, most of the mannose for glycoprotein biosynthesis in culturedhepatoma cells is derived from mannose, not glucose. Extracellular mannosemay also make a significant contribution to glycoprotein biosynthesis inthe intact organism.