Biochemistry Exam 4 Prep: Glycogen Metabolism, ETC, Oxidative Phosphorylation, Biosignaling, and Metabolic Diseases

Comprehensive vocabulary flashcards covering glycogen metabolism, ETC complexes, ATP synthase mechanisms, biosignaling cascades, and related metabolic and mitochondrial diseases from Lectures 15–19 and Recitation 10.

Hexokinase (Glycogenesis pre-step)

The enzyme that catalyzes the initial pre-step to trap glucose inside the cell by converting glucose to glucose 6-phosphate using ATP ($\text{ATP} \rightarrow \text{ADP}$).

Phosphoglucomutase

A reversible enzyme that interconverts glucose 6-phosphate and glucose 1-phosphate by moving a phosphoryl group between C6 and C1 via a transient glucose 1,6-bisphosphate intermediate.

UDP-glucose pyrophosphorylase

An enzyme that synthesizes UDP-glucose and pyrophosphate ($\text{PP}_i$) from glucose 1-phosphate and UTP ($\Delta G \approx 0$), pulled forward by inorganic pyrophosphatase hydrolyzing $\text{PP}_i \rightarrow 2\,\text{P}_i$.

Glycogenin

A primer-synthesizing core protein possessing both glycosyltransferase and synthase activities that attaches a glucose to its own tyrosine residue and extends it into a 7-unit primer.

Glycogen synthase

The pathway enzyme of glycogenesis that uses UDP-glucose to form $\alpha\text{-1,4}$ glycosidic bonds at non-reducing ends, extending chains to a maximum length of 14 units.

Branching enzyme

An enzyme that breaks an $\alpha\text{-1,4}$ glycosidic bond and transfers a 7-unit segment from the end of a chain of at least 14 units to an internal glucose, forming an $\alpha\text{-1,6}$ branch point.

Glycogen phosphorylase

An enzyme that mobilizes glycogen by phosphorolytically cleaving $\alpha\text{-1,4}$ glycosidic bonds from non-reducing ends using inorganic phosphate ($\text{P}_i$) to release glucose 1-phosphate, stopping 4 units away from a branch point.

Debranching enzyme (Transferase activity)

The catalytic activity of the debranching enzyme that recognizes a 4-unit stub left by phosphorylase and shifts 3 glucose units to the end of another chain via an $\alpha\text{-1,4}$ transfer.

Debranching enzyme (Glucosidase activity)

The catalytic activity of the debranching enzyme that hydrolyzes the remaining $\alpha\text{-1,6}$ branch-point bond, releasing 1 unit as free, unphosphorylated glucose.

Cori cycle

An inter-organ cycle that prevents futile cycling by transferring lactate produced by anaerobic glycolysis in muscle through the blood to the liver, where it is resynthesized into glucose via gluconeogenesis at a net cost of 4 ATP-equivalents per glucose.

McArdle disease (GSD V)

A muscle glycogen storage disease caused by a defect in muscle glycogen phosphorylase, preventing glycogen mobilization and causing exercise intolerance, muscle cramps, and little rise in blood lactate during intense exercise.

Tarui disease (GSD VII)

A glycogen storage disease caused by a deficiency in the muscle isoform of PFK-1 (PFKM), blocking glycolysis at the fructose 6-phosphate to fructose 1,6-bisphosphate step and leading to elevated glycogen stores, weakness, and little rise in lactate during exercise.

Reciprocal regulation (Glycogen metabolism)

A regulatory strategy where a shared covalent signal exerts opposite effects on counter-directional enzymes: phosphorylation turns glycogen phosphorylase on and glycogen synthase off, whereas dephosphorylation turns glycogen phosphorylase off and glycogen synthase on.

Liver glycogen phosphorylase

An isozyme dedicated to maintaining blood glucose; it is covalently activated by glucagon and epinephrine via phosphorylation, covalently inhibited by insulin via dephosphorylation, and directly allosterically inhibited by glucose.

Muscle glycogen phosphorylase

An isozyme dedicated to internal ATP production; it is covalently activated by epinephrine (unresponsive to glucagon), allosterically activated by AMP (R state), and allosterically inhibited by ATP and glucose 6-phosphate (T state).

Phosphorylase kinase (PhK)

A regulatory kinase activated downstream of PKA by glucagon or epinephrine that directly phosphorylates and activates glycogen phosphorylase.

Protein Phosphatase 1 (PP1)

A phosphatase stimulated downstream of insulin signaling that dephosphorylates both glycogen phosphorylase (inactivating it) and glycogen synthase (activating it), favoring glycogenesis.

Complex I (NADH dehydrogenase)

An inner mitochondrial membrane complex that accepts 2 electrons from matrix NADH via FMN and iron–sulfur (Fe–S) clusters to reduce ubiquinone, pumping 4 protons ($4\,\text{H}^+$) into the intermembrane space per electron pair.

Complex II (Succinate dehydrogenase)

A membrane-bound complex linking the citric acid cycle directly to the ETC; it oxidizes succinate to fumarate and channels electrons via FAD and Fe–S clusters to ubiquinone without pumping any protons ($0\,\text{H}^+$).

Complex III (Cytochrome c reductase / bc1 complex)

A respiratory complex that couples the oxidation of ubiquinol ($\text{QH}_2$) to the reduction of cytochrome c via the Q cycle, using hemes $b_L$, $b_H$, a Rieske Fe–S cluster, and heme $c_1$, pumping 4 protons ($4\,\text{H}^+$) into the IMS per electron pair.

Complex IV (Cytochrome c oxidase)

The terminal complex of the ETC that accepts electrons from reduced cytochrome c via $\text{Cu}_A$, heme $a$, and the heme $a_3\text{--}\text{Cu}_B$ active site to reduce $\text{O}_2$ to $2\,\text{H}_2\text{O}$, pumping 2 protons ($2\,\text{H}^+$) per pair of electrons ($4\,\text{H}^+$ per $\text{O}_2$).

Ubiquinone (Coenzyme Q)

A lipid-soluble two-electron carrier diffusing in the mitochondrial inner membrane, existing in oxidized (Q), semiquinone radical ($\text{Q}^{\bullet -}$), and fully reduced ubiquinol ($\text{QH}_2$) states.

Cytochrome c

A soluble mobile one-electron carrier located in the intermembrane space that transports electrons from Complex III to Complex IV by toggling between oxidized ($\text{Fe}^{3+}$) and reduced ($\text{Fe}^{2+}$) heme states.

Q cycle

The two-phase pathway in Complex III where two $\text{QH}_2$ molecules are oxidized at the $Q_o$ site, two cytochrome c molecules are reduced, one $\text{QH}_2$ is regenerated at the $Q_i$ site, releasing $4\,\text{H}^+$ into the IMS and consuming $2\,\text{H}^+$ from the matrix.

Thermogenin (UCP1)

A regulated physiological protein uncoupler in the inner membrane of brown adipose tissue that allows protons to re-enter the matrix without passing through ATP synthase, dissipating the proton gradient as heat.

2,4-Dinitrophenol (DNP)

A synthetic chemical uncoupler that shuttles protons across the inner mitochondrial membrane lipid bilayer, collapsing the proton-motive force, stimulating maximal $\text{O}_2$ consumption, and eliminating ATP synthesis.

Rotenone

A Complex I inhibitor that prevents electron transfer to ubiquinone, leaving Complex I reduced, accumulating NADH, and abolishing Complex I-mediated proton pumping.

Antimycin A

An inhibitor of Complex III that binds the $Q_i$ site, blocking the Q cycle, keeping Complex III reduced, and causing the semiquinone at the $Q_o$ site to leak electrons to $\text{O}_2$ to form superoxide.

Cyanide (CN-)

A toxic inhibitor that binds the heme $a_3$ iron of Complex IV, preventing $\text{O}_2$ binding and reduction, causing all upstream ETC carriers to back up in their reduced states and halting $\text{O}_2$ consumption.

Oligomycin

An inhibitor of ATP synthase that blocks the proton channel of the $F_O$ domain, causing protons to accumulate in the IMS, elevating the proton-motive force, and slowing the ETC through respiratory control.

Mitochondrial Respiration Polarographic Trace

An experimental readout measuring the relative rates of $\text{O}_2$ consumption (Line A) and ATP synthesis (Line B) across additions of substrates (succinate, $\text{ADP} + \text{P}_i$), inhibitors (oligomycin, cyanide), and uncouplers (DNP) to demonstrate chemiosmotic coupling.

Respiratory control (Acceptor control)

The physiological pacing of electron transport rate governed by ADP availability and the return of protons through ATP synthase.

F1 domain (ATP synthase)

The stationary matrix-facing catalytic component of ATP synthase composed of an $\alpha_3\beta_3$ hexamer containing three nucleotide-binding catalytic sites.

c-ring (FO domain)

The membrane-embedded rotor of ATP synthase made of hydrophobic c subunits, each containing a critical glutamate residue that protonates from the IMS and deprotonates to the matrix, driving central stalk rotation.

Loose (L) state

The conformational state of the ATP synthase $\beta$ subunit catalytic site that binds $\text{ADP} + \text{P}_i$.

Tight (T) state

The conformational state of the ATP synthase $\beta$ subunit catalytic site that brings $\text{ADP} + \text{P}_i$ together to catalyze the formation of ATP.

Open (O) state

The conformational state of the ATP synthase $\beta$ subunit catalytic site that exhibits low nucleotide affinity and releases the newly synthesized ATP molecule.

Dissociation constant (Kd)

The concentration of free ligand at which half (50%) of the receptor population is occupied; smaller values indicate higher binding affinity.

Agonist

A signaling ligand or compound that binds specifically to a receptor and induces an active conformational state to trigger a downstream cellular response.

Antagonist

A ligand that binds specifically to a receptor, preventing agonist binding and blocking pathway activation without inducing a downstream response.

Activation loop (RTK)

A flexible regulatory loop within the receptor tyrosine kinase domain that obstructs the substrate-binding cleft until autophosphorylation of three tyrosine residues forces it to swing outward, fully activating the kinase.

Kinase cascade

A signaling relay in which each activated protein kinase phosphorylates and activates multiple molecules of the next downstream kinase, providing substantial signal amplification.

Glycogen storage disease type Ia (GSD Ia)

An autosomal recessive deficiency of glucose 6-phosphatase that blocks the terminal step of both glycogenolysis and gluconeogenesis, producing severe fasting hypoglycemia, hepatomegaly, lactic acidosis, and hyperlipidemia.

Glycogen storage disease type III (GSD III)

A metabolic disorder caused by a defect in the glycogen debranching enzyme, leading to incomplete glycogenolysis, accumulation of branched limit dextrin stubs, hepatomegaly, and cardiomyopathy.

Friedreich ataxia (FRDA)

A neurodegenerative and cardiac disorder caused by a deficiency in frataxin (FXN), impairing mitochondrial iron–sulfur cluster assembly, leading to mitochondrial iron overload, dysfunction of Complexes I, II, and III, and increased ROS.

Leigh syndrome

A pediatric progressive neurodegenerative disease commonly caused by mutations in SURF1, leading to defective assembly of Complex IV (cytochrome c oxidase), ETC stalling, and increased oxidative stress.

EPI-743

A therapeutic quinone-based two-electron-transfer antioxidant cofactor that intercepts electrons leaking from stalled respiratory complexes in Leigh syndrome, attenuating reactive oxygen species.

Glutathione (GSH)

A major intracellular antioxidant tripeptide utilized by glutathione peroxidase to reduce hydrogen peroxide ($\text{H}_2\text{O}_2$) to water, regenerated by glutathione reductase using NADPH produced in the pentose phosphate pathway.