Gluconeogenesis Flashcards
Site of gluconeogenesis
In liver & kidney (cortex) to lesser extent in intestinal epithelium partly in cytoplasm & partly in mitochondria (1st step only)
Why is glucose not synthesized from simple reversal of glycolysis?
- The overall equilibrium of glycolysis strongly favours pyruvate formation
- There are 3 irreversible reactions in glycolysis which are the ones bypassed in gluconeogenesis by alternative reactions.
Thus glucose is synthesized by special pathway
List organs that require continuous glucose supply
- RBCs
- Retina
- Lens
- Brain (can use ketone bodies)
Identify conditions chch by active gluconeogenesis
Fasting: starts 4-6 hrs after last meal & reaches full capacity after depletion of liver glycogen (12-18 hrs)
DM, Cushing
Severe muscular exercise:
1. Provides lactate for Cori cycle
2. Inc sympathetic activity by CAs which stimulate gluconeogenesis
3. Dec glycogen stores & need for glucose
Mention & compare the 2 cycles related to gluconeogenesis
Both start from skeletal muscle to liver & supply substartes for gluconeogenesis (pyruvate)
1. Lactic acid cycle (Cori cycle), wash excess lactate
2. Glucose-alanine cycle (Cahill cycle), wash excess ammonia
List substrates of gluconeogenesis, their sources & corresponding intermediate
- Lactate from anaerobic glycolysis in RBCs & SKM. Pyruvate through pyruvate dehydrogenase in liver
- Glycerol from lipolysis. DHAP through phosphorylation followed by oxidation in liver cells.
- Glucogenic & mixed AAs (alanine most important) from proteolysis. Pyruvate by transdeamination of alanine in liver.
- Propionate from odd-number FFA valine, isoleucine, methionine. Succinyl CoA by 4 enzymes: acyl-CoAsynthetase, carboxylase, racemerase, mutase (vitamin B12)
Describe how glucogenic amino acids enter gluconeogenesis
Hydrolysis of tissue proteins, glucogenic amino acids generates a-keto acids, such as, a-ketoglutarate can enter TCA and form OAA, a direct precursor of PEP.
All amino acids can share in gluconeogenesis except……
Leucine & lysine
GR: Adipose tissue cannot synthesize glucose
Bec they lack glycerol kinase
Describe pathway through which propionate is converted to succinyl CoA
- Activated into propionyl CoA by acyl-CoA synthetase
- Propionyl CoA is carboxylated by propionyl CoA carboxylase to D-meythmalonyl CoA requires CO2, biotin, ATP, Mn/Mg
- Converted to L-form by racemerase
- Converted to succinyl CoA by methymalonyl-CoA mutase (isomerase) requires B12
List reactions unique to gluconeogenesis
- Carboxylation of pyruvate in mitochondria by pyruvate carboxylase (uses 1 ATP for each pyruvate)
- Decarboxylation of cytosolic oxaloacetate by PEP-carboxykinase to PEP
- Dephosphorylation of fructose 1,6 bisphosphate by fructose 1,6 bisphosphatase forming fructose 6-phosphate
- Dephosphorylation of glucose 6-phosphate by glucose 6-phosphatae releasing free glucose
Importance of pyruvate carboxylation & its coenzymes
- Provide an important substrate for gluconeogenesis
- Provide OAA that can replenish TCA cycle intermediates that may become depleted
- Overcomes irreversible conversion of PEP into pyruvate by pyruvate kinase in glycolysis
CoEs: biotin, Mn,Mg, ATP
The enzyme which aids OAA transport across mitochondria is……
Malate dehydrogenase
…..is required for PEPCK
GTP
Fructose 1,6-bisphosphatase bypasses…..of glycolysis, while glucose 6-phosphatase bypasses….
PFK-1
Hexokinase/glucokinase
Muscle gluconeogenesis doesn’t release blood glucose?
Due to absence of glucose 6-phosphatase
Describe role of covalent modification in regulation of gluconeogenesis
Glucagon & epinepherine bind its G-protein coupled receptor together with an elevation in cAMP & PKA activity leading to phosphorylation of pyruvate kinase & PEP is diverted to gluconeogenesis.
Describe role F2,6B in well-fed & fasting states
Well-fed state (under control of insulin) PFK-2 is activated (dephosphorylated) & stimulates glycolysis (by inhibiting fructose 1,6 bisphosphatase) sparing F1,6B allowing it to proceed with glycolysis
Fasting (under control of glucagon/epinepherine) PFK-2 is deactivated (phosphorylation) —fructose 2,6 bisphosphatase is activated —dec F2,6B —inhibition of glycolysis by activation fructose 1,6 bisphosphatae —inc gluconeogenesis.
……. Inhibits fructose 1,6 bisphosphatase & activates PFK1
AMP
……is an allosteric activator of pyruvate carboxylase
Acetyl CoA
…..is repressed by insulin
PEPCK
List the energy consuming steps of gluconeogensis
- Pyruvate carboxylase (ATP)
- PEPCK (GTP)
- Phosphoglycerate kinase (ATP)
- GAP kinase (NADH)
With respect gluconeogenesis energy consumption, starting with pyruvate uses….ATP, with oxaloacetate uses….., with glycerol…….
6
4
2
List the importance of gluconeogenesis
- Gluconeogenesis maintains blood glucose level esp for nervous system & erythrocytes. After an overnight fast, gluconeogenesis & glycolysis make up equal contributions to blood glucose
- Supplies glucose which is important in maintaining the level of intermediates of TCA cycle although fatty acids are the main source of acetyl coA in that case
- Clears lactate produced by muscle & erythrocytes, and glycerol produced from adipose tissue
- Glucose needed for lactose formation in mammary glands
Mention a disease of gluconeogenesis
Von Gierke disease, glucose 6-phosphatase deficiency, is usually fatal as hypoglycemia causes coma & death.
