What is gluconeogenesis?
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Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors (lactate, glucogenic amino acids, glycerol, propionate).
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What is gluconeogenesis?
Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors (lactate, glucogenic amino acids, glycerol, propionate).
Which organs perform most gluconeogenesis?
The liver (≈90%) and the kidney cortex (≈10%) are the primary sites of gluconeogenesis.
How long does liver glycogen supply blood glucose during fasting?
Liver glycogen supplies blood glucose for about 10–18 hours of fasting.
What provides blood glucose after prolonged fasting (>18 hours)?
After ≈18 hours of fasting, gluconeogenesis becomes the main source of blood glucose.
In which cellular compartments does gluconeogenesis occur?
Gluconeogenesis occurs partly in the mitochondria and partly in the cytoplasm.
How is gluconeogenesis related to glycolysis?
Gluconeogenesis is essentially the reversal of glycolysis, except for the three irreversible kinase steps which are bypassed.
Which enzyme in glycolysis is bypassed by glucose-6-phosphatase in gluconeogenesis?
Hexokinase / Glucokinase is bypassed by glucose-6-phosphatase which releases free glucose.
Which glycolytic enzyme is replaced by fructose-1,6-bisphosphatase in gluconeogenesis?
Phosphofructokinase-1 (PFK-1) is bypassed by fructose-1,6-bisphosphatase in gluconeogenesis.
Which enzymes replace pyruvate kinase in gluconeogenesis?
Pyruvate kinase is bypassed by pyruvate carboxylase and phosphoenolpyruvate carboxykinase (PEPCK).
What is the rate-limiting step of gluconeogenesis?
PEPCK (phosphoenolpyruvate carboxykinase) is described as the rate-limiting step in gluconeogenesis.
What shuttle transports oxaloacetate equivalents out of the mitochondria?
The dicarboxylic (malate) shuttle is used to transport oxaloacetate (as malate) from the mitochondria to the cytosol.
Why is the malate shuttle necessary in gluconeogenesis?
Because oxaloacetate cannot cross the mitochondrial membrane, it is converted to malate to shuttle reducing equivalents and carbon to the cytosol.
How many high-energy bonds are required to make one glucose from two lactate molecules?
Converting 2 lactate → 1 glucose requires 6 high-energy bonds.
Which enzyme converts pyruvate to oxaloacetate and what energy does it use?
Pyruvate carboxylase converts pyruvate to oxaloacetate and uses ATP (2 ATP equivalents per glucose from two pyruvate).
Which enzyme uses GTP during gluconeogenesis and at what step?
PEPCK uses GTP to convert oxaloacetate → phosphoenolpyruvate (PEP) (accounts for GTP consumption in the pathway).
Which amino acids are exceptions to being glucogenic?
All amino acids are glucogenic except leucine and lysine, which are purely ketogenic.
Can adipose tissue use glycerol for gluconeogenesis? Why or why not?
No — adipose tissue lacks glycerol kinase, so it cannot phosphorylate glycerol; glycerol is used by liver and kidney.
How many glycerol molecules are needed to form one glucose molecule?
Two glycerol molecules are required to produce one glucose.
What is required for propionate to enter the gluconeogenic pathway?
Propionate is converted to propionyl‑CoA → methylmalonyl‑CoA → succinyl‑CoA, a pathway that requires vitamin B12 for an epimerization/ rearrangement step.
List the main physiological roles of gluconeogenesis.
Gluconeogenesis maintains blood glucose during starvation/fasting/exercise and provides glucose for the brain, renal medulla, testis, fetus, muscles, and RBCs; it also removes glycerol and lactic acid to help maintain acid‑base balance.
What waste products does gluconeogenesis help clear from the body?
Gluconeogenesis helps remove glycerol (from lipolysis) and lactic acid (from anaerobic glycolysis), aiding in acid‑base control.
How do insulin and anti‑insulin hormones affect gluconeogenesis?
Insulin induces glycolytic enzymes and represses gluconeogenesis; anti‑insulin hormones (glucagon, epinephrine, cortisol) induce gluconeogenic enzymes and repress glycolysis.
Which allosteric effectors activate fructose‑1,6‑bisphosphatase?
High levels of ATP and citrate activate fructose‑1,6‑bisphosphatase, promoting gluconeogenesis.
Which metabolite activates pyruvate carboxylase?
Acetyl‑CoA is an allosteric activator of pyruvate carboxylase, stimulating the conversion of pyruvate to oxaloacetate.
Is glucose‑6‑phosphatase present in muscle and adipose tissue?
No — glucose‑6‑phosphatase is absent in muscle and adipose tissue, so these tissues cannot release free glucose.
Name the four major gluconeogenic substrates.
The four major substrates are lactate, glucogenic amino acids, glycerol, and propionate.
Which enzyme converts glycerol to glycerol‑3‑phosphate and where is it located?
Glycerol kinase converts glycerol to glycerol‑3‑phosphate and is present in the liver and kidney (not adipose).
Which enzyme converts glycerol‑3‑phosphate to dihydroxyacetone phosphate (DHAP)?
Glycerol dehydrogenase (glycerol‑3‑phosphate dehydrogenase) converts glycerol‑3‑phosphate to DHAP, using NAD+ → NADH.
What accumulates when the galactose → glucose pathway is blocked?
Excess galactose can be reduced to galactitol or oxidized to galactonic acid, which accumulate if the pathway is blocked.
Is the entry of galactose into cells insulin dependent?
No — like fructose, galactose entry into cells is not insulin dependent.
Which enzyme phosphorylates galactose to galactose‑1‑phosphate?
Galactokinase phosphorylates galactose to galactose‑1‑phosphate.
What is the most common enzyme deficiency in classic galactosemia?
Classic galactosemia most commonly results from deficiency of galactose‑1‑uridyl transferase.
What are the main clinical features of galactosemia?
Mental retardation, diarrhea, hepatomegaly, and cataracts are characteristic features of galactosemia.
Which enzyme converts galactose‑1‑phosphate to glucose‑1‑phosphate?
Galactose‑1‑uridyl transferase converts galactose‑1‑phosphate → glucose‑1‑phosphate via UDP‑glucose intermediates.
Which enzyme interconverts UDP‑galactose and UDP‑glucose?
UDP‑galactose 4‑epimerase (4‑epimerase) interconverts UDP‑galactose and UDP‑glucose.
Which tissues rely on gluconeogenesis for glucose during prolonged fasting?
The brain, renal medulla, testis, fetus, muscles, and RBCs rely on gluconeogenesis or glucose supplied by it during prolonged fasting or stress.
Name the three irreversible glycolytic kinases that must be bypassed during gluconeogenesis.
The three irreversible kinases are hexokinase/glucokinase, PFK‑1, and pyruvate kinase.
What step releases free glucose in gluconeogenesis and which enzyme performs it?
Glucose‑6‑phosphatase converts glucose‑6‑phosphate → free glucose, allowing glucose release into the bloodstream.
Which hormones are considered anti‑insulin and promote gluconeogenesis?
Glucagon, epinephrine, and cortisol are anti‑insulin hormones that promote gluconeogenesis.
Why is gluconeogenesis important for acid‑base balance?
By converting lactate (from anaerobic glycolysis) back to glucose, gluconeogenesis helps remove acid load and prevent metabolic acidosis.
What intermediate links propionate metabolism to the TCA cycle and gluconeogenesis?
Succinyl‑CoA is produced from propionate (via methylmalonyl‑CoA) and can be converted to oxaloacetate, linking to gluconeogenesis.
Which enzyme converts pyruvate to oxaloacetate in mitochondria?
Pyruvate carboxylase converts pyruvate to oxaloacetate in the mitochondria, the first step toward gluconeogenesis.
What energy‑consuming steps contribute to the 6 high‑energy bonds used to make glucose from lactate?
The major energy‑consuming steps include pyruvate carboxylase (ATP), PEPCK (GTP), and the reversal of phosphoglycerate kinase (ATP) — totaling about 6 high‑energy bonds for 2 lactate → 1 glucose.
Which tissues have glycerol kinase activity?
Liver and kidney have glycerol kinase activity and can use glycerol for gluconeogenesis; adipose tissue cannot.
How does excess galactose get metabolized when the normal pathway is blocked?
When the normal pathway is blocked, excess galactose is converted to galactitol (reduction) or galactonic acid (oxidation), which accumulate and cause toxicity.
Summarize the pathway by which propionate enters gluconeogenesis.
Propionate → propionyl‑CoA → methylmalonyl‑CoA (D→L with B12) → succinyl‑CoA → oxaloacetate → glucose, linking odd‑chain fatty acids and propionate to gluconeogenesis.
