CHAPTER 2 METABOILISM OF CARBOHYDRATE

1. Coversion into Glycogen and degradation i) Glycogenesis in which the excess glucose is converted into glycogen as a cellular storage compound. ii) Glycogenolysis involves the breakdown of glycogen into glucose, which provides a glucose supply for glucose- dependent tissues. 2. Oxidative degradation to CO2 i)Glycolysis is the pathway in which the oxidation metabolism of glucose molecules forms ATP and pyruvate. ii) Citric acid cycle in which pyruvate from glycolysis enters the citric acid cycle or Krebs cycle in aerobic organism or to lactate or alcohol in anaerobic condition and in anaerobic organisms. 3. Gluconeogenesis which is involved in the synthesis of glucose molecules from simple other compounds such as fatty acid or amino acid. Metabolic pathways of glucose

(I) COVERSION INTO GLYCOGEN AND DEGRADATION (i) GLYCOGENESIS Glycogenesis is the process of biosynthesis of glycogen from glucose and occurs mainly in muscle and liver. The following steps are involved

1. Formation of glucose 6-phosphate Glucose is phosphorylated to glucose 6-phosphate, a reaction that is common to the first reaction in the pathway of glycolysis from glucose. This reaction is catalyzed by hexokinase in muscle and glucokinase in liver. Hexokinase GlucoseGlucose + ATP → Glucose 6-phosphate + ADPGlucose

2. Conversion of Glucose 6- phosphate to glucose 1- phosphate Glucose 6- phosphate is converted to glucose 1- phosphate in a reaction catalyzed by the enzyme phosphoglucomutase. Phosphoglucomutase Glucose Glucose 6- phosphate ↔ glucose 1- phosphateglucose

3. Formation of UDPG Next, glucose 1- phosphate reacts with uridine triphosphate (UTP) to form the active nucleotide diphosphate glucose (UDPGIc) (Fig.2.1) The reaction between glucose 1- phosphate and uridine triphoaphate is catalyzed by the enzyme UDPGlc pyrophosphorylase. UDPGlc pyrophosphorylase UTP + Glucose 1- phosphate ↔ UDPGlc + PPiGlucose

4. Action of glycogen synthase By the action of the enzyme glycogen synthase, the C1 of the activated glucose of UDPGlc forms a glycosidic bond with the C4 of a terminal glucose residue of glycogen, liberating uridine diphosphate (UDP). Glycogen synthase UDPGlc + Glycogen primer( n ) → Glycogen(n+1) + UDP A preexisting glycogen molecule, or “glycogen primer”, must be present to initiate this reaction. Further glucose residues are attached in the 1-4 position to make a short chain that is acted upon by glycogen synthase. The addition of a glucose residue to a preexisting glycogen chain, or “primer,” occurs at the nonreducing, outer end of the molecule so that the “branches” of the glycogen “tree” become elongated as successive a 1-4 linkages are formed.

5. Action of Branching enzyme When the chain has been lengthened to a minimum of 11 glucose residues, a second enzyme, the branching enzyme (amylo[α 1-4 ] [α 1-6] -transglucosidase), transfers a part of the α 1-4 chain (minimum length 6 glucose residues) to a neighboring chain to form a α 1-6 linkage, thus establishing a branch point in the molecule. The branches grow by further additions of a 1-4 glucosy1 units and further branching (Fig.2.2). As the number of nonreducing terminal residues increases, the total number of reactive sites in the molecule increases, speeding up both glycogenesis and glycogenolysis.

(ii) GLYCOGENOLYSIS Glycogenolysis is the breakdown of glycogen into glucose. It is not the reverse of glycogenesis but is a separate pathway. Degradation involves a debranching mechanism. 1.Action of phosphorylase First step is catalyzed by phosphorylase Phosphorylase (C6)n + Pi ↔ (C6)n -1 + Glucose 1- phosphate glycogen glycogen This enzyme is specific for the phosphorlytic breaking (phosphorolysis; of hydrolysis) or the 1-4 linkages of glycogen to yield glucose 1-phosphate. The terminal glucosyl residues from the outermost chains of the glycogen molecule are removed sequentially until approximately four glucose residues remain on either side of a 1-6 branch.

2. Action of transferase Another enzyme (a -[1-4 ] a -[1-4 ] glucan transferase) transfers a trisaccharide unit from one branch to the other, exposing the 1-6 branch point. The hydrolytic splitting of the branch, further action by phosphorylase can proceed. The combined action of phosphorylase and these other enzymes leads to the complete breakdown of glycogen (Fig.2.3).

The reaction catalyzed by phosphoglucomutase is reversible, so that glucose 6-phophate can be formed from glucose 1- phosphate. In liver and kidney, glucose-6- phosphatase, from glucose 6- phosphate, enabling glucose to diffuse from the cell into the blood. This is the final step in hepatic glycogenolysis, which is reflected by an increase in the blood glucose.

Regulation of glycogenesis and glycogenolysis: Cyclic AMP (Fig.2.4.) integrates the regulation of glycogenolysis and glycogenesis. The principal enzymes controlling glycogen metabolism glycogen phosphorylase and glycogen synthase are regulated by a complex series of reactions involving both allosteric mechanisms and covalent modifications due to reversible phosphorylation and dephosphorylation of enzyme protein.

Many covalent modifications are due to the action of cAMP (3’,5’ - cyclic adenylic acid; cyclic AMP). cAMP is the intracellular intermediate compound or second messenger through which many hormones act. It is formed from ATP by an enzyme, adenyly1cyclase, occurring in the inner surface of cell membranes. Adenyly1 cyclase in activated by hormones such as epinephine and norepinephrine acting through β - adrenergic receptors on the cell membrane and additionally in liver by glucagon acting through an independent glucagon receptor. cAMP is destroyed by a phosphodiesterase, and it is the activity of this enzyme that maintains the normally low level of cAMP. Insulin has been reported to increase its activity in liver, thereby lowering the concentration of cAMP.

Phosphorylase differs between liver and muscle. In liver the enzyme exists in both an active and an inactive form. Active phosphorylase (phosphorylase a) has one of its serine hydroxy1 groups phosphorylated in an ester linkage. By the action of a specific phosphatase, protein phosphatase-1, the enzyme is in activated to phosphorylase b in a reaction that involves hydrolytic removal of the phosphate from the serine residue. Reactivation requires rephosphorylation with ATP and a specific enzyme, phosphorylase kinase