Caffrey Lecture 19: Carbohydrate Synthesis & Functions PDF

Synthesis of Glycosides, Lactose, Glycoproteins & Glycolipids Carbohydrates serve diverse functions in addition to being fuel sources Some of these carbohydrates are not present in the diet and need to be synthesized Carbohydrate Functions Lactose: disaccharide that is synthes...

Synthesis of Glycosides, Lactose, Glycoproteins & Glycolipids Carbohydrates serve diverse functions in addition to being fuel sources Some of these carbohydrates are not present in the diet and need to be synthesized Carbohydrate Functions Lactose: disaccharide that is synthesized in the mammary gland, provides calorie source for offspring Glycosides: sugar bound to non-sugar entity (e.g. glycoproteins and glycolipids) Glycoproteins: attached to N or O groups, found on extracellular proteins (N-glycosylation and O- glycosylation) Glycolipids: carbohydrates attached to lipids, found on the exterior of the cell membrane, serve as recognition factors (e.g. glycero-glycolipids and sphingo-glycolipids)  Precursor UDP-Glucose glucose uracil phosphates Formed from G1P by (discussed in glycogen metabolism) "Activated sugar" with multiple roles: 1. glycogen synthesis 2. attachment of glucose to proteoglycans (highly glycosylated proteins), glycoproteins or glycolipids 3. oxidized to UDP-glucuronate (precursor for polysaccharides) 4. synthesis of the disaccharide lactose (milk sugar)  Glycosyltransferases In the synthesis of glycoproteins or proteoglycans, sugars are transferred from nucleotide sugars to nucleophilic amino acid residues The nucleophilic amino acid residues include alcohols (serine and threonine) and amides (asparagine) The bond between the sugar and the nucleophilic group is a glycosidic bond Enzymes that catalyze these reactions are glycosyltransferases Glycosyltransferases play important roles in development and mutations may cause disease Bacterial glycosyltransferases are targets for inhibitors (i.e. a class of antibiotics)  Metabolic Routes of UDP-Glucuronate UDP-glucuronate is an important product of UDP-Glucose UDP glucuronate is a substrate for proteoglycans and glycoproteins, as well as other sugars and glycosides including steroids and xenobiotics *xenobiotics are compounds that are not produced naturally in humans such as drugs or carcinogens Formation of Glucuronides UDP-glucose is converted to UDP-glucuronate by UDP-glucose dehydrogenase (2 NADH are formed) UDP-glucuronate is converted to glucuronide by UDP-glucuronate transferase (in this reaction a glycosidic bond is formed) Glucuronide is water soluble, which facilitates removal of nonpolar compounds (e.g. drugs or other xenobiotics) in the urine or bile Testosterone also secreted as glucuronide (Steroid testing = Testosterone-Gluconuride in urine) How to Beat Drug Testing 1. Use another urine 2. Adulterate the sample 3. Use a diuretic to cleanse 4. Inhibit an enzyme that makes UDP-drug => Green tea may mask steroid usage Formation of Bilirubin Diglucuronide Bilirubin is a degradation product of heme (from degraded myoglobin, hemoglobin and cytochromes) The addition of hydrophilic glucuronate groups solubilizes bilirubin and allows an otherwise insoluble compound to be excreted *the accumulation of bilirubin causes jaundice, a yellowish tinge in the skin and eyes *phototherapy transforms bilirubin into a more soluble compound  Synthesis of Lactose Lactose (milk sugar) is a disaccharide of galactose and glucose Lactose is generally formed from UDP-glucose in a 2 step process 1. epimerase converts the glucose moiety to galactose (enzyme also involved in digestion of dietary galactose) 2. lactose synthase attaches galactose to the C4 of glucose (B 1,4 glycosidic linkage) Gal-Glu Pathways for Interconversion of Sugars different sugars Oligosaccharides are comprised of many different sugars Complex pathway allows many potential uses of glucose For example glucose may form glycoproteins or glycolipids, glycosaminoglycans (heparin), or sialic acid *Sialic acid is the receptor for influenza  N-Glycosylation Glycoproteins may contain complex branches of different carbohydrates (e.g. N-acetylneuraminic acid, galactose, N-acetylglucosamine, mannose, fucose) Sequence of carbohydrates similar to sequence of amino acids  Fates of Glycoproteins & Proteoglycans Glycoproteins are made in the ER and secreted from the Golgi to the plasma membrane On the cell surface they often function as receptors Some of the glycoproteins are secreted or sent to the lysosome (glycosyl groups protect protein from lysosomal enzymes)  Carbohydrates & Influenza 1918 flu pandemic killed ~100 million worldwide Influenza entry and exit related to sialic acid on cells Treatment = inhibition of viral neuraminidase (an enzyme that degrades sialic acid and allows egress)  Carbohydrates and Blood Groups Carbohydrates found on RBCs determine blood group Type determined by carbohydrate antigen present (A, B, AB, or O=no A or B) Antibodies then determine what RBC or plasma can be accepted: for RBC O can accept O, A can accept A or O, B can accept B or O, and AB can accept A, B, AB, and O Blood Groups-Continued The antigenic determinant is boxed, Type O has neither (R=glycolipids and glycoproteins) *Other blood groups determined by other carbohydrate patterns (e.g. Rh negative or positive) *GlcNAc = N-acetylglucosamine, Gal = galactose, Fuc = fucose, GalNAc = N- acetylgalatosamine