TBL 10: Gluconeogenesis, Fructose & Galactose Metabolism

Bypass 1

pyruvate carboxylase

• located in mitochondria

• adds a carbon to pyruvate w/ CO2 to form oxaloacetate [OAA]

• irreversible

• requires biotin [vitamin B7] & ATP

  • inhibited by avidin [raw egg white]

Bypass 2

phosphoenolpyruvate carboxykinase [PEPCK]

• mostly cytosolic

• synth phosphoenolpyruvate [PEP] from OAA

• reversible rxn

  • requires GTP

• OAA must be transported from mitochondria via malate & aspartate shuttles [inefficiency]

  • must convert OAA to asp or malate and then back to OAA

Bypass 3

fructose-1,6-biphosphatase

• dephosphorylates fructose-1,6-BP to fructose-6-phosphate

• rate-limiting step for gluconeogenesis

• reversal of rxn catalyzed by PFK1

• called futile cycle because generates heat

Bypass 4

glucose-6-phosphatase

• ER membrane

• dephosphorylates glucose-6-P to free glucose

• opp. of hexokinase

• rxn irreversible & regulated

Alcohol & anemia impairs gluconeogenesis by

• glycerol-3-P & lactate as glucogenic substrates require NAD+ to proceed

  • alcohol or low O2 [anemia] → shift NAD+ to NADH

Cori cycle

mech. by which lactate generate in muscle during anaerobic glycolysis can be used for glucose synthesis in liver

• during recovery from exercise

  • lactate goes to liver & is reconverted to pyruvate

  • liver uses pyruvate to generate glucose

  • glucose exported by liver back to muscle

*1/2 of all gluconeogenesis!

glucose-alanine cycle

transport glucogenic substrate from muscle to liver [& ammonia for urea cycle]

• pyruvate transaminated [add NH3] to alanine in muscle

• alanine exported to liver

• alanine transaminated back to pyruvate [NH3 removed by urea cycle]

• pyruvate converted to glucose

• glucose exported to skeletal muscle

*1/3 of gluconeogenesis

Lipodosis

glycerol

• from hydrolysis of adipose triglycerides [in fasting state] → 1 glycerol & 3 FAs

• glycerol kinase

  • phosphorylates glycerol → glycerol-3-phosphate

• glycerol-3-P dehydrogenase

  • converts glycerol-3-P to dihydroxyacetone phosphate

    • → F-1,6-BP

Glutamine

imp renal substrate

• several systems produce glutamine via glutamine synthetase

• its readily converted to OAA

• removal of NH3 from glutamine → glucose

  • imp for gluconeogenesis in kidney!

  • 1/3 of glucose production!

which organ produces most of glucose from gluconeogenesis [liver or kidney?]

liver

Metformin

• biguanide class drug

• 1st line treatment for diabetes

• → defective cAMP & PKA → high AMP, less ATP → interferes with glucagon signaling

• primary effect:

  • decrease hepatic gluconeogenesis prod.

  • decrease intestinal abs of glucose

  • increase peripheral glucose uptake & utilization

pyruvate carboxylase deficiency

• causes build-up of gluconeogenesis carbon sources

• can lead to lactic acidosis

• hypoglycemia a constant issue

which carbon source for gluconeogenesis does not need to go through the pathway producing pyruvate?

glycerol

sucrose =

fructose + glucose

3 steps of fructose metabolism

1. fructokinase

   1. phosphorylates fructose-1-phosphate

      1. can’t leave cell bc of phosphate

2. aldolase B

   1. F-1-P → glyceraldehyde & dihydroxyacetone phosphate

   2. liver specific

   3. rate limiting step in fructose metabolism

   4. bypasses PFK1 reaction

3. triose kinase

   1. addition of P makes 2nd glycolysis/gluconeogenic intmd

Fructokinase deficiency/ essential fructosuria

• fructose not phosphorylated, accumulates in urine

  • free to leave cell

• benign [no consequences]

heriditary fructose intolerance / aldolase B deficiency

• fructose-1-P accumulates

  • decrease in ATP concentration bc traps intracellular phosphate

    • phosphate unavail for ATP synth

  • hyperuricemia

  • impaired glycolysis, gluconeogenesis, glycogen breakdown

    • severe hypoglycemia, lactic acidosis, jaundice

    • → liver & kidney damage

• treatment: remove fructose & sucrose from diet

Lactose =

galactose + glucose

Galactose Metabolism

1. galactokinase [GALK]

   1. phosphorylation to galactose-1-phosphate

2. galactose-1-phosphate uridyltransferase [GALT]

   1. epimerization of galactose-1-P to glucose-1-P

3. phosphoglucose mutase [PGM]

   1. glucose-1-P converted to glucose-6-phosphate

Classic galactosemia [Type I]

GALT deficiency

• digestive problems, vomiting [shortly after breastfeeding], liver damage, cataracts, irreversible cognitive disability if not addressed

• galactokinase product inhibition

  • galactose leaves cell, accumulates in blood & urine [galactosemia & galactosuria]

• MOST SEVERE

Type II Galactosemia

galactokinase [GALK] deficiency

• galactose free to leave cell → galactosemia & galactosuria

• cataracts

Cataract formation in galactosemia

aldose reductase catalyzes reduction of excess galactose to galactitol, which accumulates in the eye