Pathways

Manidipine is a dihydropyridine calcium channel blocker used to treat hypertension. It is used clinically as an antihypertensive. It is selective for vasculature and does not produce effects on the heart at clinically relevant dosages. Contraction of vascular smooth muscle is stimulated by Gq coupled receptors which produce calcium release from the sarcoplasmic reticulum. This is followed by opening of voltage dependent calcium channels and an influx of calcium into the cell ultimately producing contraction. Manidipine binds to and dissociates slowly from L- and T-type voltage dependent calcium channels on smooth muscle cells, blocking the entrance of extracellular calcium into the cell and preventing this contraction. This produces vasodilation which decreases blood pressure. Manidipine produces renal vasodilation and an increase in natriuresis. This likely contributes to the antihypertensive effect by reducing blood volume. Possible side effects of using manidipine may include dizziness, flushing, headache, and hypotension.

Mannitol busulfan is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Mannitol busulfan passes through the liver and is then excreted from the body mainly through the kidney.

Escherichia coli can utilize D-mannose for its sole carbon and energy source. Alpha-D-mannose is introduced into the cytoplasm through a mannose PTS permease. A phosphotransferase system (PTS) takes up mannose producing D-mannose-6-phosphate which is then converted to D-fructose-6-phosphate via an isomerase. D-fructose-6-phosphate is an intermediate of glycolysis and can enter the pathways of metabolism. The first two enzymes in the pathway catalyze isomerizations that interconvert phosphorylated aldohexoses (β-D-glucose-6-phosphate, D-mannose-6-phosphate) and phosphorylated ketohexoses (D-fructose-6-phosphate). The reaction catalyzed by mannose-6-phosphate isomerase that produces D-mannose-6-phosphate is the first committed step in the biosynthesis of the activated mannose donor GDP-α-D-mannose. D-mannose-6-phosphate is then converted to GDP-D-mannose by the interaction of phosphomannomutase and mannose-1-phosphate guanylyltransferase. GDP-D-mannose produces GDP-L-fucose beginning with the dehydration to GDP-4-dehydro-6-deoxy-D-mannose. GDP-fucose is synthesized by a two step epimerase and reductase of GDP-4-dehydro-6-deoxy-D-mannose. L-fucose then enters the colanic acid building blocks biosynthesis pathway.

Mannose is a sugar monomer of the aldohexose series of carbohydrates and is a C-2 epimer of glucose. It is a key monosaccharide for protein and lipid glycosylation . The majority of mannose metabolism takes place in the cytosol. There are two routes to form mannose 6-phosphate. The first subpathway involves using beta-D-fructose 6-phosphate from glycolysis. The enzyme mannose-6-phosphate isomerase catalyzes the interconversion of beta-D-fructose 6-phosphate and D-mannose 6-phosphate. It requires a zinc ion as a cofactor. The second subpathway involves using the secreted enzyme, mannan endo-1,4-beta-mannosidase to catalyze the random hydrolysis of (1->4)-beta-D-mannosidic linkages in mannans to form D-mannose residues. These D-mannose residues are then imported into the cell cytoplasm via a sugar transport protein (a sugar/hydrogen symporter). Once inside the cell, hexokinase catalyzes the conversion of D-mannose into D-mannose 6-phosphate. Next, phosphomannomutase catalyzes the interconversion of D-mannose 6-phosphate and D-mannose 1-phosphate. However, D-mannose 1-phosphate can also be synthesized from ADP-mannose in the chloroplast via nudix hydrolase 14 and a magnesium or manganese ion cofactor. D-mannose 1-phosphate is then transported into the cytosol by a predicted D-mannose 1-phosphate transporter. Next, mannose-1-phosphate guanylyltransferase uses GTP to catalyze the conversion of D-mannose 1-phosphate into GDP-mannose. This is followed by GDP-mannose 4,6 dehydratase catalyzing the conversion of GDP-mannose into GDP-4-dehydro-6-deoxy-D-mannose. It requires NADP as a cofactor. Last, GDP-L-fucose synthase catalyzes the conversion of GDP-4-dehydro-6-deoxy-D-mannose into GDP-L-fucose.