CARBOHYDRATE/LIPID METABOLISM Akinniyi A. Osuntoki, Ph.D. Department of Biochemistry Faculty of Basic Medical Sciences College of Medicine of The University of Lagos

METABOLISM WHAT IS METABOLISM ? CATABOLISM ANABOLISM

WHAT IS THE ROLE OF METABOLISM? Energy generation Bioconversion Biosynthesis

CARBOHYDRATES Carbohydrates are the most abundant class of biological molecules Carbohydrates are important fuel molecules. Carbohydrates are easier to metabolize than fats or amino acids Glucose (C 6 H 12 O 6 )is so important that the level is used as the main control for insulin, the central metabolic hormone

OVERVIEW Carbohydrates have the general formula (CH 2 O) n Some carbohydrates are monomers while others contain two or more monomers joined by covalent bonds. The disaccharides, oligosaccharides and polysaccharide must be broken down into the constituent monomers before absorption and utilization by cells. Glucose is the most important monosaccharide; the major pathways of carbohydrate metabolism begins or end with glucose If an enzyme required to process a certain carbohydrate is missing, the sugar accumulates in the body causing problems.

CATABOLISM Some simple carbohydrates have their own enzymatic oxidation pathways Disaccharides, oligosaccharides and polysaccharides are typically broken down into components by enzymes In most organisms, excess carbohydrates are regularly catabolized to acetyl CoA Acetyl CoA is a feedstock for the synthesis of fatty acids, triglycerides, lipids. The monosaccharide units enter major metabolic pathways GLYCOLYSIS is the pathway used by all body cells to extract part of the chemical energy in the glucose molecule Glycolysis converts glucose to pyruvate

Pyruvate can be completely oxidized to CO 2 and H 2 0 in the krebs cycle in aerobic organisms PENTOSE PHOSPHATE PATHWAY- Conversion of hexoses into pentoses. Production of ribose and NADPH GLYCOGENOLYSIS- The breakdown of glycogen into glucose, which provides glucose supply for dependent tissues

GLYCOLYSIS

OTHER PROMINENT MONOSACCHARIDES Glucose is primary end product of starch and glycogen digestion 3 other hexoses are prominent digestion products Fructose: from fruits and sucrose Galactose: from lactose Mannose: from digestion of polysaccharides and glycoproteins Their metabolism involves conversion to glycolytic products

FEEDER PATHWAYS FOR GLYCOLYSIS

ANABOLISM GLYCOGENESIS-Conversion of excess into glycogen as a cellular storage mechanism. Prevents excess osmotic pressure buildup inside the cell GLUCONEOGENESIS- Synthesis of glucose from non carbohydrate precursors.

DISORDERS OF CARBOHYDRATE METABOLISM Occurs in many forms Inborn errors of metabolism Acquired/ secondary derangements in carbohydrate metabolism e.g. diabetic ketoacidosis

INBORN ERRORS OF CARBOHYDRATE METABOLISM Carbohydrates account for a major portion of the human diet metabolized into three main monosaccharides glucose, fructose and galactose failure to effectively utilise these molecules is associated with themajority of the inborn errors of carbohydrates metabolism.

Galactosemia. Lactose intolerance Glycogen storage diseases

REGULATION OF METABOLISM It is not all enzymes in a metabolic pathway that have their activity regulated Metabolic regulation is effected by modulating the activity of one or more key enzymes One enzyme-catalyzed reaction called the rate-limiting step- is usually slower than the others. The rate limiting step has an effect on the rate of formation of the final product Another key regulatory step is the commitment step. This is the first irreversible pathway unique to the pathway. The rate- limiting step may not be the committing step.

LIPIDS Play indispensable role in cell stucture and metabolism Lipids have several cellular functions Provide energy Supply essential fatty acids Serve as reservoirs of lipid soluble vitamins Most of the dietary fat is triacylglycerides

TRIACYGLYCEROL O CH 2 O C R O R 1 C O C H O CH 2 O C R 2

HYDROLYSIS OF TRIACYLGLYCEROL The major site of triacylglycerols digestion is the small intestine. Some lipases remove fatty acyl groups from either C-1 or C-3. Pancreatic lipase does not hydrolyse the fatty acyl group C-2.

β-OXIDATION Fatty acids are degraded by the β-oxidation pathway The pathway involves the sequential removal of two-carbon fragments from a fatty acid chain. Free fatty acids must be activated by condensation with coenzyme A before they can be oxidized. The β-oxidation of the fatty acyl CoA occurs in the mitochondrial matrix. Short-chain fatty acids (2-10 Carbon atoms) can cross the mitochondrial membranes. Long chain fatty acids are activated on the outer mitochondrial membrane and transported into the matrix by a shuttle system which employes carnitine as an acyl carrier.

PRINCIPAL REACTIONS IN β-OXIDATION Activation First dehydrogenation (FAD is coenzyme). Hydration Second Dehydrogenation (NAD + is coenzyme) Thiolysis

The oxidation of even chain fatty acids produce acetyl CoA molecules. Propionyl CoA is produced in the final step of odd-chain fatty acids. The propionyl CoA is converted to succinyl CoA.

KETONE BODIES Provide energy for muscle tissue. The use is regulated by fluctuations in the concentration of blood glucose. When glucose is high insulin release is stimulated and glucose entry into muscle is facilitated. When glucose is low, insulin level decreases and less glucose enter muscle tissue. Fatty acids and ketone bodies are then exported from the liver to muscle tissue where they serve as fuel.

When glucose level is low for a long time, organs like the brain that normally use only glucose utilize fatty acids and ketone bodies as fuel. This may lead to ketosis, a condition in which the production of ketone bodies exceeds use by the peripheral tissues. Excess ketone bodies in the blood can cause acidosis, a decrease in blood pH. If not alleviated, acidosis leads to coma and sometimes death.

KETONE BODIES Acetoacetate 3-hydroxybutyrate Acetone

SYNTHESIS Apart from two poly unsaturated fatty acids, the human body is able to synthesize all other fatty acids required for either structural or storage properties Any metabolite that yields acetyl CoA during its degradation is a potential supplier for lipogenesis Fatty acid biosynthesis is a reductive process requiring NADPH Lipogenesis occurs in the cytoplasm

ESSENTIAL FATTY ACIDS Linoleic acid and linolenic acid are considered essential fatty acids because they cannot be synthesized by humans. Linoleic acid (18:2n-6) Linolenic acid (18:3n-3) The abbreviation shows the chemical structure. 18:3 shows there are 3 double bonds n-6 implies that the first double bond is between carbon 6 and 7 when counting from the CH3 end i.e an ω6 fatty acid

The essential fatty acids are substrates for the endogenous synthesis of other fatty acid required for many physiological processes including the synthesis of prostaglandins and leukotrienes.

ATP PRODUCTION IN TCA CYCLE Step 4 1 NADH = 3ATP Step 6 1 NADH= 3ATP Step 7 1 GTP = 1 ATP Step 8 1 FADH2= 2ATP Step 10 1 NADH = 3 ATP NET TOTAL = 12 ATP