gluconeogenesis

gluconeogenesis

→ to make “new” glucose molecules

• lactate → pyruvate is reverse of fermentation, pyruvate moves into the pathway

• glucogenic amino acid metabolites come from the urea cycle and move into the pathway

• triglycerides → glycerol is fatty acid metabolism, glycerol moves into the pathway

• CO₂ → 3-PG is the calvin cycle 3-PG moves into the pathway for plants

fates of synthesized carbs

• release glucose directly into blood (animals)

• glycogenesis → production of glycogen for carbohydrate storage (animals)

• creation of glycoproteins

• monosaccharide and disaccharide production

• starch production → carb storage (plants)

• sucrose (plants)

glycolysis v. gluconeogenesis

• irreversible rxns of glycolysis must be bypassed by gluconeogenesis

  • no ATP generated during gluconeogenesis

  • different enzymes in some steps

  • different regulation to prevent a futile cycle

• occurs in different tissues

• first two steps of gluconeogenesis do NOT match glycolysis

pyruvate carboxylase

bicarbonate + pyruvate → oxaloacetate

• EC: 6, ligase

• catalytic strategy: covalent

• chem logic: add C-C bond

• energy consuming step

  • ATP is used → ADP + Pi

• biotin cofactor — moves bicarbonate

  • covalently linked to enzyme via Lys residue

    • site 1: bicarbonate is converted to CO₂ (w/ ATP) and attaches to biotin

    • site 2: CO₂ is released and reacts w/ pyruvate to form oxaloacetate

  • exists on a flexible arm that carries an intermediate

• requires transport into mitochondria (where the enzyme is)

phosphoenolpyruvate (PEP) carboxykinase

oxaloacetate + GTP → phosphoenolpyruvate

• EC: 4, lyase

• chem logic: break C-C bond, transfer P

• energy consuming step (GTP → GDP)

• 2 step reaction

  • phosphorylation by GTP

  • decarboxylation

  • occurs in mitochondria or cytosol

• removes carbon added in step 1

• creates a bypass for pyruvate kinase (glycolysis) putting new exergonic steps in place of irreversible step

first two steps of gluconeogenesis in the mitochondria

• inner mitochondrial membrane is selectively permeable

  • oxaloacetate cannot escape

• oxaloacetate can be used in citric acid cycle if needed

• oxaloacetate can be converted to PEP or malate to allow transport to cytosol for gluconeogenesis

steps 3-8

reverse reactions of steps 4-9 of glycolysis

• enolase

• PGM

• PGK

• GAPDH

• TPI

• aldolase

→ 2 phosphoenolpyruvate to 1 fructose 1,6 bisphosphate

fructose 1,6-bisphosphatase-1

fructose 1,6 bisphosphate → fructose 6-phosphate

• EC: 3, hydrolase

• chem logic: group transfer, Pi goes to an H

• cleaves w/ water

• inversely regulated w/ PFK-1

  • bypass step

• does not generate ATP, makes Pi

phosphohexose isomerase

fructose-6-phosphate → glucose-6-phosphate

• EC:

• chem logic: rearrangement

• low energy step, form of isomerization

• makes an aldose from a ketose

• reverse rxn of step 2 of glycolysis

glucose-6-phosphatase

G6P → glucose

• EC: 3, hydrolase

• chem logic: group transfer

• opposite rxn from hexokinase

  • 3rd bypass step

• does not produce ATP, just Pi

• segregated in ER

net process

• costs 4 ATP, 2 GTP and 2 NADH

• physiologically necessary:

  • brain, nervous system, RBCs generate ATP only from glucose

• allows generation of glucose when glycogen stores are depleted:

  • during starvation

  • during vigorous exercise

  • can generate glucose from amino acids, but not fatty acids