Gluconeogenesis & Glycogen metabolism

Rate-limiting enzyme of glycogenolysis

Glycogen phosphorylase

Coenzyme required by glycogen phosphorylase

Pyridoxal phosphate (PLP / Vitamin B6)

Primary product formed by glycogen phosphorylase cleavage

Glucose-1-phosphate (G1P)

Linear glycosidic bond connecting glucosyl units in glycogen

α(1→4) glycosidic bond

Branch point linkage in glycogen structure

α(1→6) glycosidic bond

Number of glucosyl residues remaining per branch before glycogen phosphorylase stops

4 glucosyl residues (phosphorylase limit dextrin)

Enzymatic activity of the debranching enzyme that transfers 3 glucosyl units

α-1

Enzymatic activity of the debranching enzyme that cleaves the single branch glucose

Amylo-α(1→6)-glucosidase

Product released specifically by amylo-α(1→6)-glucosidase

Free glucose

Approximate ratio of G1P to free glucose released during glycogenolysis

8:1

Enzyme that interconverts glucose-1-phosphate and glucose-6-phosphate

Phosphoglucomutase

Enzyme present in the liver that releases free glucose into the blood from G6P

Glucose-6-phosphatase

Reason skeletal muscle cannot release free glucose into systemic circulation

Lacks glucose-6-phosphatase

Primary physiological role of liver glycogen

Maintaining blood/plasma glucose levels during fasting

Primary physiological role of muscle glycogen

Providing a readily available source of ATP/G1P for muscle contraction

Substrate converted by UDP-glucose pyrophosphorylase along with UTP

Glucose-1-phosphate (G1P)

High-energy glucosyl donor for glycogen synthesis

UDP-glucose

Side product of UDP-glucose synthesis hydrolyzed to drive the reaction forward

Inorganic pyrophosphate (PPi)

Protein primer required for de novo glycogen synthesis

Glycogenin

Specific amino acid residue on glycogenin that receives initial glucose units

Tyrosine (Tyr-194)

Number of glucosyl residues transferred autoproteolytically by glycogenin

7 to 8 glucose residues

Rate-limiting enzyme of glycogenesis

Glycogen synthase

Type of bond synthesized directly by glycogen synthase

α(1→4) glycosidic bond

Enzyme that introduces branch points into the growing glycogen molecule

Branching enzyme (amylo-α(1→4)→α(1→6)-transglucosidase / 4:6 transferase)

Minimum length of a growing chain required before the branching enzyme can act

At least 11 glucosyl residues

Advantage of a highly branched glycogen structure

Increases solubility and provides multiple nonreducing ends for rapid degradation and synthesis

Hormone that stimulates glycogen synthesis in the fed state

Insulin

Hormones that stimulate glycogen breakdown in liver and muscle during fasting or stress

Glucagon (liver) and Epinephrine (liver and muscle)

Second messenger produced upon glucagon or epinephrine receptor binding

Cyclic AMP (cAMP)

Enzyme synthesized by adenylyl cyclase that activates protein kinase A

cAMP

Downstream kinase activated directly by Protein Kinase A in glycogenolysis

Phosphorylase kinase

Active state of glycogen phosphorylase produced by phosphorylation

Phosphorylase a

Inactive

dephosphorylated state of glycogen phosphorylase

Active form of glycogen synthase (unphosphorylated)

Glycogen synthase a

Inactive form of glycogen synthase (phosphorylated)

Glycogen synthase b

Enzyme activated by insulin that dephosphorylates glycogen synthase and phosphorylase

Protein phosphatase-1 (PP1)

Enzyme activated by insulin that degrades cAMP to 5'-AMP

Phosphodiesterase

Allosteric activator of muscle glycogen phosphorylase b that acts without phosphorylation

5'-AMP

Allosteric inhibitor of glycogen phosphorylase in the liver and muscle

ATP and Glucose-6-phosphate (and free glucose in liver)

Allosteric activator of glycogen synthase b

Glucose-6-phosphate (G6P)

Ion released during muscle contraction that allosterically activates phosphorylase kinase

Calcium (Ca2+)

Subunit of phosphorylase kinase that binds calcium ions

Calmodulin

Protein phosphorylated by PKA that acts to inhibit protein phosphatase-1

Inhibitor-1 (Inhibitor-1-phosphate)

Inherited enzyme deficiency in Von Gierke disease (GSD Type Ia)

Glucose-6-phosphatase

Gene mutated in Von Gierke disease (GSD Type Ia)

G6PC

Hallmark clinical features of Von Gierke disease

Severe fasting hypoglycemia

Inherited enzyme deficiency in Pompe disease (GSD Type II)

Lysosomal α(1→4) and α(1→6) glucosidase (acid maltase)

Gene mutated in Pompe disease (GSD Type II)

GAA

Hallmark clinical features of infantile Pompe disease

Cardiomegaly/heart failure by age 2

Inherited enzyme deficiency in Cori or Forbes disease (GSD Type III)

Debranching enzyme (amylo-α(1→6)-glucosidase / transferase)

Gene mutated in Cori disease (GSD Type III)

AGL

Structural characteristic of glycogen accumulated in Cori disease

Abnormally short outer branches (limit dextrin-like)

Inherited enzyme deficiency in Andersen disease / Amylopectinosis (GSD Type IV)

Branching enzyme (amylo-α(1→4)→α(1→6)-transglucosidase)

Gene mutated in Andersen disease (GSD Type IV)

GBE1

Structural characteristic of glycogen accumulated in Andersen disease

Abnormally long linear chains with few branch points (amylopectin-like)

Clinical outcome typically seen in Andersen disease

Hepatosplenomegaly

Inherited enzyme deficiency in McArdle syndrome (GSD Type V)

Muscle glycogen phosphorylase (myophosphorylase)

Gene mutated in McArdle syndrome (GSD Type V)

PYGM

Hallmark clinical findings of McArdle syndrome

Exercise intolerance

Inherited enzyme deficiency in Hers disease (GSD Type VI)

Liver glycogen phosphorylase

Gene mutated in Hers disease (GSD Type VI)

PYGL

Clinical presentation of Hers disease compared to Von Gierke disease

Mild fasting hypoglycemia and hepatomegaly with generally benign prognosis

Inherited enzyme deficiency in Tarui disease (GSD Type VII)

Muscle phosphofructokinase-1 (PFK-1 / M-isozyme)

Primary organ site of gluconeogenesis contributing approximately 90% of endogenous glucose

Liver

Secondary organ that contributes ~10% of gluconeogenesis in overnight fasting (increasing during prolonged starvation)

Kidney (renal cortex)

Cellular compartments in which gluconeogenesis takes place

Mitochondria and cytosol

Primary non-carbohydrate carbon precursors for gluconeogenesis

Lactate

Metabolic cycle in which muscle lactate is transported to the liver for gluconeogenesis

Cori cycle (lactic acid cycle)

Metabolic cycle transferring alanine from muscle to liver to yield pyruvate and urea

Glucose-alanine cycle

Enzyme converting glycerol to glycerol-3-phosphate in the liver

Glycerol kinase

Enzyme converting glycerol-3-phosphate to dihydroxyacetone phosphate (DHAP)

Glycerol-3-phosphate dehydrogenase

Reason even-chain fatty acids cannot produce net glucose

Pyruvate dehydrogenase reaction is irreversible (acetyl-CoA cannot form net pyruvate)

Only two strictly ketogenic amino acids that cannot serve as gluconeogenic substrates

Leucine and Lysine

First bypass reaction of gluconeogenesis: Enzyme converting pyruvate to oxaloacetate

Pyruvate carboxylase

Cellular location of pyruvate carboxylase

Mitochondria

Coenzyme and energy required by pyruvate carboxylase

Biotin and ATP

Obligate allosteric activator of pyruvate carboxylase

Acetyl-CoA

Intermediate used to shuttle oxaloacetate out of mitochondria into the cytosol

Malate

Enzyme reducing oxaloacetate to malate and re-oxidizing it in the cytosol

Malate dehydrogenase

Second enzyme of the first bypass: converts oxaloacetate to phosphoenolpyruvate

Phosphoenolpyruvate carboxykinase (PEPCK)

High-energy nucleotide used by PEPCK to generate PEP

GTP

Glycolytic enzyme bypassed by the combined actions of Pyruvate Carboxylase and PEPCK

Pyruvate kinase

Rate-limiting enzyme of gluconeogenesis

Fructose-1

Reaction catalyzed by Fructose-1

6-bisphosphatase

Glycolytic enzyme bypassed by Fructose-1

6-bisphosphatase

Most potent allosteric inhibitor of FBPase-1 and activator of PFK-1

Fructose-2

Allosteric inhibitor of FBPase-1 that indicates low cellular energy

AMP

Allosteric activators of Fructose-1

6-bisphosphatase

Final bypass enzyme of gluconeogenesis converting G6P to free glucose

Glucose-6-phosphatase

Cellular organelle membrane where glucose-6-phosphatase is located

Endoplasmic reticulum (ER) membrane

Transporter required to move glucose-6-phosphate into the lumen of the ER

Glucose-6-phosphate translocase

Glycolytic enzyme bypassed by Glucose-6-phosphatase

Hexokinase / Glucokinase

Net number of high-energy phosphate bonds consumed to produce 1 mole of glucose from 2 moles of pyruvate

6 high-energy bonds (4 ATP + 2 GTP)

Transcription factor mediated by cAMP that increases PEPCK gene expression

CREB (cAMP Response Element-Binding protein)

Effect of glucagon on hepatic pyruvate kinase activity

Inactivates it via PKA-dependent phosphorylation (prevents futile cycling)

Key metabolic intermediate that accumulates during fasting and stimulates gluconeogenesis while inhibiting PDH

Acetyl-CoA

Normal plasma glucose concentration range in the healthy fasting state

3.5 to 5.5 mmol/L (or < 126 mg/dL)

Normal plasma glucose concentration range in the fed state

6.5 to 7.2 mmol/L (or < 200 mg/dL)

Primary hormone dominating the fed state to promote fuel storage

Insulin

Primary hormone dominating early fasting to stimulate glycogenolysis and gluconeogenesis

Glucagon