Gluconeogenesis - Steps, Regulation and Significance

Vocabulary flashcards covering gluconeogenesis pathways, substrates, key enzymes, regulation, and related clinical conditions based on the medical biochemistry lecture.

gluconeogenesis

A series of metabolic events that allows for the production of glucose from noncarbohydrate precursors.

fructose 1,6-bisphosphatase

The rate-limiting enzyme in gluconeogenesis that catalyzes the exergonic hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate.

Renal Cortex Gluconeogenesis

The gluconeogenic process in the kidney that provides $10\%$ of blood glucose after an overnight fast and up to $40\%$ during prolonged starvation ($10\text{--}40$ days).

Skeletal Muscle Gluconeogenesis Lack

The inability of skeletal muscle to participate in gluconeogenesis due to the complete absence of the enzyme glucose 6-phosphatase.

Thermodynamic Barriers of Glycolysis

The three nonequilibrium reactions in glycolysis catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase that prevent simple reversal for glucose synthesis.

Pyruvate Carboxylase

A mitochondrial ABC enzyme requiring ATP, biotin, and CO₂ to catalyze the carboxylation of pyruvate to oxaloacetate.

ABC Enzyme Requirement

The metabolic requirement for ATP, Biotin (vitamin B7), and $\text{CO}_2$ utilized by enzymes such as mitochondrial pyruvate carboxylase.

Acetyl-CoA (in Gluconeogenesis)

An obligate allosteric activator of pyruvate carboxylase produced during fatty acid oxidation in the fasting state.

Oxaloacetate Transport Shuttle

The mechanism in which mitochondrial oxaloacetate is reduced to malate by NADH-linked malate dehydrogenase, transported across the mitochondrial membrane, and reoxidized to oxaloacetate in the cytosol.

Phosphoenolpyruvate Carboxykinase (PEPCK)

The cytosolic enzyme that catalyzes the decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate using GTP as the phosphate donor.

CREB-Leucine Zipper Mechanism

The transcriptional activation pathway triggered by glucagon via cAMP that increases gene expression of phosphoenolpyruvate carboxykinase (PEPCK).

Steroid Hormone Receptor-Zinc Finger Motif

The nuclear receptor mechanism utilized by cortisol to bind DNA and induce gene expression of phosphoenolpyruvate carboxykinase (PEPCK).

Fructose 2,6-bisphosphate

An allosteric effector that activates phosphofructokinase-1 and inhibits fructose 1,6-bisphosphatase, whose levels decrease during fasting to promote gluconeogenesis.

Bifunctional Enzyme Phosphorylation

The cAMP-dependent protein kinase A phosphorylation of the PFK-2/FBPase-2 enzyme complex triggered by glucagon, which activates FBPase-2 and lowers fructose 2,6-bisphosphate levels.

Glucose 6-phosphatase

An enzyme located in the endoplasmic reticulum membrane that hydrolyzes inorganic phosphate from glucose 6-phosphate to release free glucose into the blood.

Lactate

A major gluconeogenic substrate generated by anaerobic glycolysis in active skeletal muscle and red blood cells that is converted to pyruvate by lactate dehydrogenase in the liver.

Cori Cycle

The metabolic pathway in which lactate produced by active skeletal muscle or red blood cells is transported to the liver, converted to glucose via gluconeogenesis, and returned to peripheral tissues.

Glucogenic Amino Acids

Amino acids released during muscle protein breakdown that enter gluconeogenesis by conversion into $\alpha$-keto acids such as oxaloacetate or $\alpha$-ketoglutarate.

Glucose-Alanine Cycle

A pathway in which muscle protein is degraded to alanine, transported to the liver to form pyruvate for gluconeogenesis, and returns glucose to muscle for ATP production.

Glycerol

A gluconeogenic precursor released from adipose tissue triacylglycerol hydrolysis that is phosphorylated by liver glycerol kinase and oxidized to dihydroxyacetone phosphate (DHAP).

Adipose Glycerol Kinase Absence

The absence of glycerol kinase in adipocytes, which prevents them from directly re-esterifying free glycerol released during lipolysis into triacylglycerols.

Propionyl-CoA

A gluconeogenic intermediate produced from odd-chain fatty acid $\beta$-oxidation and VOMIT amino acids that is carboxylated to succinyl-CoA.

VOMIT Metabolism

The catabolic pathway of Valine, Odd-chain fatty acids, Methionine, Isoleucine, and Threonine converting them into propionyl-CoA and subsequently succinyl-CoA for gluconeogenesis.

Succinyl-CoA Functions

A metabolic intermediate that functions in the citric acid cycle, gluconeogenesis, heme synthesis, and myelin synthesis.

Cortisol Effect on PEPCK

Genetic induction of liver phosphoenolpyruvate carboxykinase (PEPCK) expression, which increases the $V_{\max}$ of the enzyme and enhances gluconeogenesis.

Energetic Requirement of Gluconeogenesis

The net consumption of $4\,\text{ATP}$, $2\,\text{GTP}$, and $2\,\text{NADH}$ to synthesize one molecule of glucose from two molecules of pyruvate.

Alcoholic Hypoglycemia

Hypoglycemia caused by alcohol consumption, where excessive cytosolic NADH produced by ethanol metabolism depletes pyruvate and oxaloacetate, inhibiting gluconeogenesis.

Ethanol-Induced Lactic Acidosis

An elevation in blood lactate resulting from ethanol metabolism increasing the cytosolic $\text{NADH}/\text{NAD}^+$ ratio, which shifts lactate dehydrogenase toward lactate production.

Ethanol-Induced Hepatosteatosis

Fatty liver caused by elevated $\text{NADH}/\text{NAD}^+$ ratios from ethanol oxidation, which shifts dihydroxyacetone phosphate (DHAP) to glycerol 3-phosphate and stimulates lipogenesis.

Hypoglycemia in Babies of Diabetic Mothers

Neonatal hypoglycemia caused by fetal hyperplasia of pancreatic islet cells in response to maternal hyperglycemia, leading to unsuppressed high insulin levels after delivery.

Renal Glutamine Metabolism

The utilization of glutamine in the renal cortex as the preferred precursor for renal gluconeogenesis during severe hypoglycemia or liver failure.

Pyruvate Carboxylase Deficiency

An autosomal recessive disorder presenting with lactic acidosis, hypoglycemia, ketoacidosis, and hyperammonemia due to an inability to convert pyruvate to oxaloacetate.

Avidin Toxicity

Inhibition of gluconeogenesis caused by consuming raw egg whites containing avidin, which binds biotin (vitamin B7) and prevents pyruvate carboxylase activity.

Ingestion of Ackee Fruit

Consumption of hypoglycin from ackee fruit, which inhibits fatty acid oxidation, lowering acetyl-CoA levels and inhibiting pyruvate carboxylase.

Von Gierke's Disease

An inherited metabolic disorder caused by glucose 6-phosphatase deficiency, impairing both gluconeogenesis and glycogenolysis.

MCAD Deficiency Gluconeogenesis Effect

Impairment of gluconeogenesis resulting from medium-chain acyl-CoA dehydrogenase deficiency, which decreases fatty acid oxidation and acetyl-CoA production.

Intracellular Phosphate Trapping

Depletion of cellular ATP occurring in inherited fructose intolerance or galactosemia, which inhibits energy-requiring pathways including gluconeogenesis.

Biotin (Vitamin B7)

An essential vitamin cofactor required by pyruvate carboxylase for carbon dioxide fixation during the initial step of gluconeogenesis.

Malate Dehydrogenase

An enzyme that interconverts oxaloacetate and malate in both mitochondria and cytosol to allow oxaloacetate equivalents to cross the inner mitochondrial membrane.

Hexokinase Bypass

The final reaction of gluconeogenesis in which glucose 6-phosphatase hydrolyzes glucose 6-phosphate to bypass the irreversible hexokinase/glucokinase reaction of glycolysis.

Phosphofructokinase-1 Bypass

The gluconeogenic reaction catalyzed by fructose 1,6-bisphosphatase that hydrolyzes fructose 1,6-bisphosphate to fructose 6-phosphate, bypassing the irreversible PFK-1 reaction.

Pyruvate Kinase Bypass

The two-step gluconeogenic pathway using pyruvate carboxylase and PEPCK to convert pyruvate to phosphoenolpyruvate, bypassing the irreversible pyruvate kinase reaction.

Methylprednisolone

A synthetic anti-inflammatory glucocorticoid that induces PEPCK expression and peripheral amino acid release, causing drug-induced hyperglycemia.

Dihydroxyacetone Phosphate (DHAP)

A triose phosphate intermediate formed either from fructose 1,6-bisphosphate cleavage or from glycerol 3-phosphate oxidation in gluconeogenesis.

Alanine Transaminase (ALT)

The liver enzyme that converts alanine and $\alpha$-ketoglutarate to pyruvate and glutamate in the glucose-alanine cycle.

Ethanol-Induced Ketoacidosis

Ketoacidosis caused by high $\text{NADH}/\text{NAD}^+$ ratios disfavoring the TCA cycle, resulting in excess acetyl-CoA utilization for ketone body synthesis.

Substrate Availability Regulation

The regulation of gluconeogenesis rate primarily determined by the rate of precursor release (lactate, glycerol, amino acids) from peripheral tissues.

Low Insulin-to-Glucagon Ratio

The hormonal state during fasting that increases cAMP and activates protein kinase A, inducing gluconeogenic enzymes and repressing glycolytic enzymes.

Endoplasmic Reticulum Glucose Transport

The transport mechanism in the ER membrane that allows free glucose produced by glucose 6-phosphatase to cross into the cytosol and blood.

Reciprocal Regulation of Fructose 2,6-bisphosphate

The hormonal control mechanism where insulin increases fructose 2,6-bisphosphate to promote glycolysis, while glucagon decreases it to activate fructose 1,6-bisphosphatase and promote gluconeogenesis.