Recording-2025-09-29T17:01:15.462Z

Glycolysis, Pyruvate Oxidation, and the Citric Acid Cycle (Overview and Key Outputs)

  • Main flow of cellular respiration: glycolysis -> pyruvate oxidation -> citric acid cycle (CAC) -> oxidative phosphorylation (ETC and chemiosmosis).

  • Net entry and exit in glycolysis:

    • Input: one molecule of glucose.
    • Output: 2 pyruvate, 2 ATP (net), 2 NADH; all in the cytosol.
    • Location: cytosol (cytoplasm).
    • Summary equation (net):
      \text{Glucose} + 2\ NAD^+ + 2\ ADP + 2\ Pi \rightarrow 2\ Pyruvate + 2\ NADH + 2\ ATP + 2\ H2O + 2\ H^+.

  • Pyruvate oxidation (link step) in the mitochondrion:

    • Input: 2 pyruvate (from glycolysis).
    • Location: mitochondrial matrix (across outer and inner membranes).
    • Output per glucose: 2 CO₂, 2 acetyl-CoA, 2 NADH; ATP produced: 0.
    • Overall per glucose: 2\ \text{pyruvate} + 2\ \text{CoA} + 2\ NAD^+ \rightarrow 2\ \text{acetyl-CoA} + 2\ CO_2 + 2\ NADH.

  • Citric acid cycle (CAC, Krebs cycle) per acetyl-CoA:

    • Per acetyl-CoA input: generates 3 NADH, 1 FADH₂, and 1 GTP (substrate-level ATP).
    • Per glucose (two acetyl-CoAs): 6 NADH, 2 FADH₂, 2 GTP, and 4 CO₂.
    • Overall per glucose: 2\ \text{Acetyl- CoA} \rightarrow 4\ CO2 + 6\ NADH + 2\ FADH2 + 2\ GTP.

  • Big picture energy summary (so far):

    • Carbon atoms from glucose are fully oxidized to CO₂ by CAC; 6 carbons from glucose become CO₂ (2 in pyruvate oxidation, 4 in CAC).
    • Electron carriers reduced: NADH (10 total per glucose: 2 from glycolysis + 2 from pyruvate oxidation + 6 from CAC) and FADH₂ (2 total from CAC).
    • Direct ATP yield up to this point: 4 ATP via substrate-level phosphorylation (2 from glycolysis and 2 from CAC as GTP).
    • Overall energy transformation goal: convert chemical energy from nutrients into energy stored in ATP.

  • Oxidative phosphorylation (ETC + chemiosmosis):

    • Input carriers: 10 NADH and 2 FADH₂ per glucose.
    • Where the energy lives: high-energy electrons drive proton pumping across the inner mitochondrial membrane, creating a proton (H⁺) gradient (proton motive force).
    • Terminal electron acceptor: molecular oxygen (O₂). Reduced O₂ forms water (H₂O).
    • Main result: use the proton gradient to drive ATP synthase (chemiosmosis) to synthesize ATP.
    • Important distinction: the electron transport chain itself does not synthesize most ATP; ATP synthase does.
    • ATP synthase mechanism:
    • Structure: multi-subunit rotary enzyme embedded in the inner mitochondrial membrane; gamma (γ) subunit rotates and perturbs surrounding beta (β) subunits.
    • Conformational changes in β subunits (driven by γ rotation) facilitate catalytic formation of ATP from ADP and Pi.
    • The rotary motion is powered by flow of H⁺ down its gradient through the enzyme.
    • Energy yield notes:
    • Theoretical maximum ATP per glucose (oxidative phosphorylation + substrate-level): commonly quoted as 36–38 ATP per glucose.
    • Real cellular yields are typically about 29–30 ATP per glucose due to costs of NADH shuttling into mitochondria, NADH used in other pathways, and other mitochondrial/work costs.
    • Why NADH yields differ: NADH electrons entering at Complex I contribute more to the gradient (through Complexes I, III, IV) than FADH₂ electrons entering at Complex II (through Complexes III and IV only).
    • Total electron carriers and ATP synthesis are interconnected with transport costs for NADH from cytosol to mitochondria and for ATP/ADP exchange between compartments.

  • Electron transport chain (ETC) details (key components and flow):

    • Major protein complexes (embedded in inner mitochondrial membrane): Complex I, Complex II, Complex III, Complex IV.
    • Mobile carriers: ubiquinone (Q) and cytochrome c.
    • Electron flow: NADH donates to Complex I; FADH₂ donates to Complex II; electrons pass from Complex I or II to ubiquinone (Q) → Complex III → cytochrome c → Complex IV → O₂.
    • Oxygen as final electron acceptor: completes the chain to form water.
    • Proton pumping: electron transfer through Complexes I, III, and IV pumps protons across the membrane, creating the proton gradient.
    • Gradient energy is stored as potential energy (proton-motive force) and used by ATP synthase.
    • The difference in entry points (NADH to Complex I vs FADH₂ to Complex II) leads to different contributions to the proton gradient and ATP yield.

  • Important conceptual distinctions and takeaways

    • ETC vs ATP synthase: ETC accepts and moves electrons and builds the gradient; ATP synthase uses the gradient to synthesize ATP. The ETC does not by itself produce most ATP.
    • Substrate-level phosphorylation vs oxidative phosphorylation:
    • Substrate-level phosphorylation (early steps): ATP formed directly from a phosphorylated intermediate transferring a phosphate to ADP (glycolysis and CAC).
    • Oxidative phosphorylation (late steps): ATP formed via ATP synthase powered by the proton gradient generated by the ETC.
    • Spinning turbine metaphor vs real enzyme: ATP synthase is a rotary enzyme that uses ion flow to drive conformational changes and catalysis; there are no literal spinning turbines in cells.

  • Beyond glucose: entry points for other nutrients into central metabolism

    • Carbohydrates: complex carbs/fats break down to monosaccharides and funnel into glycolysis.
    • Glycerol (from fats): glycerol can be converted into a glycolysis intermediate and enter glycolysis as a 3-carbon node.
    • Fatty acids: β-oxidation clips fatty acids into 2-carbon fragments that form acetyl-CoA; each fragment enters CAC; typical outputs per 2-carbon fragment include 2 CO₂, 3 NADH, 1 FADH₂, and 1 ATP (via CAC).
    • Proteins: amino acids feed into CAC at various entry points depending on their side chains, but ultimately channel into the same core pathways.
    • Overall concept: different nutrients can be shuttled into glycolysis, CAC, and oxidative phosphorylation to generate ATP.

  • Anaerobic metabolism (absence of oxygen): two main strategies
    1) Anaerobic respiration (in certain bacteria/archaea):

    • Electron transport chain runs, but the final electron acceptor is not O₂ (e.g., nitrate, NO₃⁻; in the example, nitrate reductase transfers electrons to nitrate).
    • End result still uses a proton gradient to drive ATP synthase; location is typically the cell membrane (not mitochondria, since bacteria lack mitochondria).
    • Example: E. coli uses nitrate reductase to reduce nitrate to nitrite.
    • Overall: glycolysis remains, continues to feed electrons into a non-oxygen terminal acceptor via an ETC.
      2) Fermentation (when organisms cannot switch to another terminal electron acceptor):
    • Purpose: keep glycolysis running by regenerating NAD⁺ from NADH when the ETC is not functioning due to lack of oxygen.
    • Two common pathways:
      • Lactic acid fermentation: Pyruvate is reduced to lactate by lactate dehydrogenase, consuming NADH and regenerating NAD⁺; allows glycolysis to continue and produce a small amount of ATP.
      • Net: glucose → 2 pyruvate → 2 lactate; NADH consumed, NAD⁺ regenerated.
      • Ethanol fermentation (yeast): Pyruvate is converted to acetaldehyde (releasing CO₂) and then to ethanol, consuming NADH and regenerating NAD⁺; glycolysis can continue.
      • Net: glucose → 2 pyruvate → 2 acetaldehyde → 2 ethanol; NADH consumed, NAD⁺ regenerated.
    • Outcome: glycolysis continues with at least some ATP production, but without full oxidative phosphorylation.

  • Photosynthesis: overview, energy bookkeeping, and cellular context

    • Overall transformation: carbon dioxide and water, using light energy, are converted into carbohydrates (organic carbon) and oxygen gas is released.
    • Net equation (simplified):
      6\ CO2 + 6\ H2O + \text{light energy} \rightarrow C6H{12}O6 + 6\ O2.
    • Free energy aspect: ΔG for overall photosynthesis is endergonic with a large positive value:
      \Delta G = +686\ \text{kcal mol}^{-1}.
    • Light energy as the ultimate energy source; energy is captured and transformed into chemical energy stored in ATP and NADPH.
    • Two major stages of photosynthesis:
    • Light reactions (in the thylakoid membranes): convert light energy into chemical energy (ATP and NADPH) and release O₂ from water.
    • Calvin cycle (in the stroma): uses ATP and NADPH to fix CO₂ into carbohydrates (builds sugar).
    • Autotrophs vs Heterotrophs:
    • Autotrophs: self-feeders; build organic molecules (e.g., plants, algae) using light energy.
    • Heterotrophs: rely on consuming organic molecules produced by autotrophs or other organisms.
    • Plant anatomy context: chloroplasts in mesophyll cells, stomata on leaf surfaces for gas exchange; thylakoid membranes and stroma compartments inside chloroplasts.
    • Pigments and light absorption:
    • Chlorophyll (types a and b): primary pigments; absorb blue and red light most effectively.
    • Carotenoids (e.g., beta-carotene): accessory pigments, appear yellow/orange; broaden