CH 14

Question 1

Why is glucose central to metabolism across life?

Answer 1

It met multiple selective criteria: plausible prebiotic availability (e.g., “glyoxylose” chemistry), aqueous stability (mostly cyclic glucopyranose), excellent stepwise redox yield, and metabolic flexibility as a branch point for energy, biosynthesis, and polymer formation.

Question 2

What evidence suggests glycolysis is ancient?

Answer 2

It’s nearly universal in Bacteria, Archaea, and Eukarya, implying emergence before atmospheric O₂, then conservation in LUCA by purifying selection.

Question 3

Name the three primary anabolic carbohydrate pathways in non‑photosynthetic organisms.

Answer 3

Pentose phosphate pathway (PPP), gluconeogenesis, glycogen degradation & synthesis.

Question 4

What are the primary results of the PPP?

Answer 4

(1) NADPH generation for reductive biosynthesis & ROS defense, (2) ribose‑5‑P for nucleotides/coenzymes (ATP, NAD⁺/NADP⁺, FAD, CoA), (3) erythrose‑4‑P for aromatic amino acids.

Question 5

Which PPP phase makes NADPH and which interconverts sugars?

Answer 5

Oxidative phase makes NADPH; non‑oxidative phase interconverts C3–C7 sugars, producing R5P and regenerating G6P.

Question 6

Why is the PPP called metabolically flexible?

Answer 6

Flux shifts to match needs: more NADPH, more R5P, or recycling G6P to sustain NADPH production.

Question 7

Oxidative phase net (for 6 G6P)?

Answer 7

6 G6P + 12 NADP⁺ + 6 H₂O → 6 ribulose‑5‑P + 12 NADPH + 12 H⁺ + 6 CO₂.

Question 8

Non‑oxidative phase carbon shuffle (overall)?

Answer 8

6 ribulose‑5‑P → 4 fructose‑6‑P + 2 glyceraldehyde‑3‑P.

Question 9

Overall PPP net (combining phases)?

Answer 9

6 G6P + 12 NADP⁺ + 6 H₂O → 4 F6P + 2 G3P + 12 NADPH + 12 H⁺ + 6 CO₂.

Question 10

Name the commitment step enzyme of the PPP and its output per G6P.

Answer 10

G6PD; oxidative phase yields 2 NADPH and 1 CO₂ per G6P to ribulose‑5‑P.

Question 11

What do transketolase and transaldolase transfer?

Answer 11

Transketolase transfers C2 units (TPP‑dependent); transaldolase transfers C3 units—together generating F6P and G3P from pentoses.

Question 12

How does the PPP regenerate G6P for continued NADPH production?

Answer 12

The non‑oxidative phase + gluconeogenic/glycolytic enzymes (phosphoglucoisomerase, triose‑P isomerase, aldolase, FBPase‑1) convert pentoses → 5 G6P from 6 ribulose‑5‑P.

Question 13

How is G6PD regulated by NADP⁺/NADPH?

Answer 13

High NADP⁺ allosterically activates G6PD (PPP ↑); high NADPH inhibits G6PD (PPP ↓, glycolysis flux ↑).

Question 14

Why is NADPH crucial for RBCs?

Answer 14

It fuels glutathione reductase: GSSG + NADPH → 2 GSH, keeping glutathione reduced (GSH) to detoxify ROS via glutathione peroxidase.

Question 15

What happens in G6PD deficiency under oxidative stress (e.g., primaquine, vicine in fava beans)?

Answer 15

Inadequate NADPH → low GSH → ROS accumulate → hemolysis, Heinz bodies, hemolytic anemia.

Question 16

Why are RBCs especially sensitive to G6PD deficiency?

Answer 16

They lack mitochondria and rely heavily on the PPP for NADPH; insufficient NADPH compromises antioxidant defenses.

Question 17

What is gluconeogenesis and why do animals need it?

Answer 17

A multi‑step pathway that synthesizes glucose from non‑carbohydrate precursors (lactate, amino acids, glycerol) to supply glucose‑dependent tissues (especially brain and erythrocytes) when dietary glucose or glycogen is insufficient.

Question 18

How many steps of gluconeogenesis are shared with glycolysis, and which are not?

Answer 18

Seven steps are the reversible reactions shared with glycolysis; three glycolytic “irreversible” steps are bypassed by special gluconeogenic enzymes.

Question 19

List the three glycolytic steps that must be bypassed in gluconeogenesis.

Answer 19

Hexokinase, PFK‑1, and pyruvate kinase steps are bypassed (they are highly exergonic in glycolysis).

Question 20

What four enzymes perform the three bypasses in gluconeogenesis?

Answer 20

(1) Pyruvate carboxylase and (2) PEP carboxykinase (pyruvate → oxaloacetate → PEP), (3) FBPase‑1 (F‑1,6‑BP → F‑6‑P), (4) Glucose‑6‑phosphatase (G‑6‑P → glucose).

Question 21

What are the major carbon sources feeding gluconeogenesis in animals?

Answer 21

Lactate (from anaerobic glycolysis), glucogenic amino acids (to pyruvate/TCA intermediates), and glycerol (from triacylglycerol lipolysis → DHAP).

Question 22

How do plants leverage gluconeogenesis?

Answer 22

They convert glyceraldehyde‑3‑phosphate (from the Calvin‑Benson cycle) to glucose for sucrose and starch synthesis.

Question 23

What is the Cori cycle and why is it important?

Answer 23

A liver–muscle shuttle: muscle produces lactate (anaerobic glycolysis) → liver converts lactate back to glucose (gluconeogenesis) → glucose returns to muscle; net cost = 4 ATP equivalents in liver.

Question 24

What is the overall net reaction of gluconeogenesis (from 2 pyruvate)?

Answer 24

2 pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H⁺ + 4 H₂O → glucose + 4 ADP + 2 GDP + 6 Pᵢ + 2 NAD⁺.

Question 25

What is the energy cost of converting "glucose → 2 pyruvate → glucose" (round‑trip)?

Answer 25

Cancelling terms across glycolysis and gluconeogenesis gives: 2 ATP + 2 GTP + 2 H₂O → 2 ADP + 2 GDP + 4 Pᵢ (i.e., gluconeogenesis is expensive).

Question 26

Which compartments are involved in the first bypass (pyruvate → PEP)?

Answer 26

Mitochondria (pyruvate carboxylase makes oxaloacetate) and cytosol/mitochondria (PEP carboxykinase makes PEP), depending on tissue and conditions.

Question 27

What is a futile (substrate) cycle, and why must cells avoid it between glycolysis and gluconeogenesis?

Answer 27

Simultaneous opposing flux (e.g., kinase vs phosphatase) that burns ATP/GTP → heat without net product; if both pathways ran fast together, energy would be wasted.

Question 28

Give the net energy‑waste equations for the two potential futile cycles highlighted.

Answer 28

(1) 2 ATP + 2 H₂O → 2 ADP + 2 Pᵢ + heat; (2) 2 GTP → 2 GDP + 2 Pᵢ + heat.

Question 29

What three strategies cells use to prevent glycolysis & gluconeogenesis from running together?

Answer 29

Allosteric control, covalent modification (phosphorylation), and compartmentalization (e.g., hexokinase in cytosol vs G‑6‑phosphatase in ER lumen with T1/T2/T3 transporters and GLUT2 at the plasma membrane).

Question 30

How do energy charge and citrate tune the two pathways (key control points)?

Answer 30

High AMP/ADP → PFK‑1↑, pyruvate kinase↑, and gluconeogenic enzymes↓; high ATP/citrate/acetyl‑CoA → PFK‑1 & pyruvate kinase↓ and pyruvate carboxylase & FBPase‑1↑.

Question 31

What is fructose‑2,6‑bisphosphate (F‑2,6‑BP) and its dual regulatory effects?

Answer 31

A potent allosteric signal: activates PFK‑1 (dramatically increases apparent substrate affinity) and inhibits FBPase‑1 (decreases its apparent affinity), thereby favoring glycolysis over gluconeogenesis.

Question 32

How do insulin and glucagon control F‑2,6‑BP levels via the PFK‑2/FBPase‑2 bifunctional enzyme?

Answer 32

Insulin → dephosphorylation → PFK‑2 active → F‑2,6‑BP ↑ → glycolysis ↑. Glucagon → phosphorylation → FBPase‑2 active → F‑2,6‑BP ↓ → gluconeogenesis ↑.

Question 33

What is the physiological purpose of glycogen in liver vs muscle?

Answer 33

Liver glycogen buffers blood glucose (short‑term store and release). Muscle glycogen provides a local, rapid fuel for contraction (anaerobic & aerobic) and is not exported.

Question 34

What is the net reaction for glycogen degradation (one step at a non‑reducing end)?

Answer 34

Glycogenₙ + Pi → Glycogenₙ₋₁ + glucose‑1‑phosphate (G1P).

Question 35

What is the overall reaction for glycogen synthesis (adding one residue)?

Answer 35

Glycogenₙ + G1P + ATP + H₂O → Glycogenₙ₊₁ + ADP + 2 Pi (energy cost via UDP‑glucose formation & PPi hydrolysis).

Question 36

Name the three key reaction types and their enzymes in glycogen metabolism.

Answer 36

(1) Glycogen phosphorylase (phosphorolysis → G1P), (2) Glycogen synthase (chain elongation from UDP‑glucose), (3) Branching & debranching enzymes (set/remove α(1→6) branches to optimize non‑reducing ends).

Question 37

How does glycogen phosphorylase work and where does it stop?

Answer 37

It uses PLP to processively cleave α(1→4) bonds from non‑reducing ends, generating G1P, and halts 4 residues before an α(1→6) branch.

Question 38

What two activities does the debranching enzyme contain, and what products result?

Answer 38

Transferase moves a trisaccharide block to a nearby chain; α‑1,6‑glucosidase then cleaves the remaining branch glucose as free glucose (contrast with phosphorylase's G1P).

Question 39

What is the immediate product of phosphorylase and how is it routed in muscle vs liver?

Answer 39

G1P → G6P (via phosphoglucomutase). Muscle: G6P enters glycolysis. Liver: G6P is dephosphorylated in the ER by G6Pase and exported as glucose.

Question 40

How is UDP‑glucose generated for glycogen synthesis and why is the reaction favorable?

Answer 40

G1P + UTP → UDP‑glucose + PPi (UDP‑glucose pyrophosphorylase); PPi → 2 Pi drives the reaction forward; UDP → UTP is regenerated by nucleotide diphosphate kinase.

Question 41

What does the glycogen branching enzyme do and why does branching matter?

Answer 41

Transfers a heptasaccharide (~7 residues) to form a new α(1→6) branch ≥4 residues from another branch; branching increases solubility and multiplies non‑reducing ends → faster synthesis & degradation.

Question 42

How is glycogen synthase regulated by phosphorylation and allostery?

Answer 42

Unphosphorylated = R‑state (active); phosphorylated = T‑state (inactive). Glucose‑6‑P binding allosterically activates the enzyme by a large conformational change.

Question 43

How do epinephrine and glucagon acutely affect glycogen metabolism in liver?

Answer 43

They activate PKA → phosphorylase kinase, which phosphorylates & activates glycogen phosphorylase (degradation ↑) and phosphorylates & inhibits glycogen synthase (synthesis ↓).

Question 44

How does insulin shift glycogen metabolism after a meal?

Answer 44

Insulin activates protein phosphatase 1 (PP1) → dephosphorylates & activates glycogen synthase while dephosphorylating & inactivating glycogen phosphorylase → synthesis ↑, breakdown ↓.

Question 45

Summarize the delayed hormonal regulation model shown for liver.

Answer 45

Glucagon → PKA → phosphorylase kinase → phosphorylase (active) & synthase (inactive); Insulin → PP1 → synthase (active) & phosphorylase (inactive). Net effect ensures one direction dominates at a time.

Question 46

What is the functional difference between glucose release from phosphorylase vs debranching enzyme steps?

Answer 46

Phosphorylase releases G1P (phosphate retained), while α‑1,6‑glucosidase of the debranching enzyme releases free glucose at branch points.

Question 47

What everyday strategy can double muscle glycogen within ~24 h, and how?

Answer 47

Carbohydrate loading: brief intense exercise to deplete glycogen, followed by ~10 g carbohydrate/kg body mass → supercompensation of muscle glycogen.

Question 48

Give examples of glycogen storage diseases (GSDs) and the defective step.

Answer 48

Type I (Von Gierke): glucose‑6‑phosphatase deficiency; Type II (Pompe): acid α‑glucosidase deficiency; Type V (McArdle): muscle phosphorylase deficiency; all cause characteristic glycogen accumulation/usage defects.

Question 49

In which cellular compartment is glucose‑6‑phosphatase located and what transporters support it?

Answer 49

ER lumen; T1 imports G6P, T2 exports Pi, T3 exports glucose; GLUT2 handles plasma membrane glucose exchange in liver.

Question 50

Why does adding branches ≥4 residues away from an existing branch matter structurally?

Answer 50

It preserves optimal packing and accessibility of chains, ensuring enough linear length for phosphorylase and synthase to operate efficiently while maximizing new non‑reducing ends.