Gluconeogenesis

Formation of glucose from non carbohydrate precursors like • pyruvate • lactate • glycerol • glucogenic a.a • propionyl CoA During starvation and late fasting

Organ location: in liver and less in kidney Cellular location: partly mitochondrial and partly cytosol

It is as reversal of the glycolysis but there is some energy barriers that prevents this reverse but can be treated and they are :- • pyruvate kinase ** pyruvate carboxylase PEP carboxykinase • PFK -1 **** fructose 1,6 biphosphatase • glucokinase ** glucose 6 phosphatase in liver and kidney and absent in muscle

Pyruvate is converted to OAA by pyruvate carboxylase ( biotin and ATP ) in mitochondria And then converted to PEP by PEP caroxykinase in cytosol But OAA is unable to be transported to cytosol so it is converted to malate by mitochondrial MD ( NADH ~> NAD ) as malate can cross to cytosol and then it is re oxidized to OAA by cytosolic MD ( NAD ~> NADH)

2 pyruvate + 6 ATP + 2NADH ~> glucose + 6 ADP + 2NAD

*( NADH /NAD) ~> oxaloacetate to malate * ( NAD/ NADH) ~> malate to OAA راحوا مع بعض * ( NADH / NAD) ~> 1,3 biphosphoglycerate to glyceraldehyde 3 p =1 NADH / NAD • ATP / ADP ~> pyruvate carboxylase • ATP / ADP ~> PEP carboxykinase • ATP / ADP ~> phosphoglycerate kinase = 3 ATP /ADP To form glucose we need 2 pyruvate So it is 2 NADH AND 6 ATP CONSUMED So it

1- lactate By lactate dehydrogenase, lactate is formed in sk ms and RBC is transported to liver and converted to pyruvate through cori cycle 2- glucogenic a.a • They are ( alanine - aspartic acid - glutamic acid etc) • In starvation and DM , they are transaminated to the corresponding carbon skeletons and then enter TCA to give OAA and then glucose • Alanine in muscle is a major substrate • Alanine is transported to liver and transaminated to pyruvate and then pyruvate convert to glucose, glucose can enter glycolysis and produce pyruvate that is transaminated to alanine and so on ( alanine cycle Glycerol : results from lipolysis of TAG in adipose tissue , glycerol kinase in liver and other tissues except adipose tissue and muscles convert it to glycerol 3 phosphate that can convert to DAHP by glycerol 3 phosphate dehydrogenase Propionyl CoA : results from oxidation of odd f.a chain and carbon skeletalon of some a.a ( isoleucine- valine - methionine) and then converted to succinyl CoA but is a minor source for glucose ( قولي ازاي )

Key enzymes: pyruvate carboxylase and PEP carboxykinase and fructose 1,6 biphosphatase and glucose 6 phosphatase When Glycolysis is active , gluconeogensis is inactive Gene expression ( long term) 1- hyperglycemic hormones : g hormones stimulates all key enzymes 2- insulin inhibits them Short term ( Allosteric effect) Pyruvate carboxylase : activated by acetyl CoA Fructose 1,6 biphosphatase : activated by ATP and citrate and inhibited by AMP and fructose 2,6 biphosphate

1-The process of gluconeogenesis is important for Glucose supply when carbohydrates are not available in the diet. • Continuous supply of glucose is especially im- portant for: a. Nervous system b. Erythrocytes c.Skeletal muscle especially under anaerobic conditions d. Formation of lactose, the milk sugar, in mammary glands e.Glucose is the only fuel for fetus. 3-Glucose is also important for maintaining ctric acid cycle, as it is the main source of pyruvate 4-Gluconeogenic process is used to clear the body from lactate that is formed in sk ms during exercise and Rbcs ( cori cycle)