Principles of bioenergetics and fuel molecule metabolism

Most MCAT sugars are D-sugars (the OH on the highest-numbered chiral carbon points right in a Fischer projection). Epimers differ at exactly one chiral carbon (glucose vs. galactose at C4; glucose vs. mannose at C2); enantiomers are mirror images at every center (D- vs. L-glucose). In the ring, the anomeric carbon (the former carbonyl) is α (its OH trans to the CH₂OH reference) or β (cis). The ring constantly opens and recloses, interconverting α and β through the open chain — mutarotation.

A glycosidic linkage forms between the anomeric carbon of one sugar and a hydroxyl of another, releasing water; hydrolysis (by intestinal glycosidases) breaks it. Know the famous three by parts and linkage: maltose = glc-(α1→4)-glc; sucrose = glc-(α1↔2)-fru; lactose = gal-(β1→4)-glc. Lactase deficiency (lactose intolerance) is the classic missing-glycosidase example.

Starch = α-1,4 glucose chains; amylose is unbranched, amylopectin is branched at α-1,6 points. Glycogen is like amylopectin but more highly branched, giving many ends for fast mobilization — ideal for animal storage (see glycogen metabolism). Cellulose is β-1,4 glucose; humans lack the enzyme for β-linkages, so it passes through as fiber. The α-vs-β linkage is the entire reason starch is food and cellulose is roughage.

The ring's anomeric carbon is a hemiacetal that can open to a reactive carbonyl; that carbonyl is what gets oxidized (reducing the reagent). Benedict's/Fehling's turns brick-red; Tollens' forms a silver mirror. Maltose and lactose keep a free anomeric carbon, so they reduce; in sucrose both anomeric carbons are locked in the glycosidic bond, making it a non-reducing sugar — a favorite distractor.

Fatty acids are saturated (no C=C, pack tightly, solid — animal fat) or unsaturated (cis C=C kink the chain, lower melting point — oils). Triglycerides form by ester bonds (dehydration) between glycerol's three hydroxyls and three fatty acids; they store more than twice the energy per gram of carbohydrate because they are so reduced. Base hydrolysis of a triglyceride — saponification — yields glycerol + fatty-acid salts (soap). Their breakdown for fuel is β-oxidation.

The steroid nucleus is three six-membered rings plus one five-membered ring. Cholesterol sits in membranes (see fluidity) and is the raw material the body converts into cortisol, aldosterone, estrogen, and testosterone (the steroid hormones of 3A), into bile salts for fat emulsification, and into vitamin D. Being lipophilic, steroid hormones cross membranes and act on intracellular receptors.

A (vision — retinal pigment); D (calcium absorption / bone — made from cholesterol in skin); E (antioxidant protecting membranes); K (synthesis of blood-clotting factors). Because they're stored rather than excreted, excess can build up — the reason these (not vitamin C) are the classic hypervitaminosis examples.

ΔG = ΔH − TΔS. A negative ΔG means the reaction releases usable energy and can proceed; a positive ΔG means it needs an energy input. Note ΔG says nothing about speed — that's kinetics (enzymes). Cells keep many reactions far from equilibrium so they keep running, and pay for endergonic steps by coupling them to a strongly exergonic one (usually ATP hydrolysis).

ATP stores energy in phosphoanhydride bonds; breaking the terminal one releases a large, usable amount of free energy. Coupling an endergonic reaction to ATP hydrolysis makes the combined ΔG negative, so it proceeds — this is how cells run biosynthesis, transport, and movement. ATP is constantly regenerated (you cycle your body weight in ATP daily), mostly by oxidative phosphorylation.

Remember OIL RIG (Oxidation Is Loss, Reduction Is Gain of electrons) and LEO the lion says GER (Lose Electrons = Oxidized; Gain = Reduced). As glucose is oxidized, its electrons are picked up by NAD⁺ (becoming NADH) and FAD (becoming FADH₂). These carriers are the link between the early pathways and the ATP-making electron transport chain — they carry the energy of the electrons, which is cashed in during oxidative phosphorylation.

Glycolysis needs a supply of NAD⁺; aerobically, the electron transport chain regenerates it. Anaerobically it can't, so fermentation reduces pyruvate (or acetaldehyde) to dump the electrons from NADH, regenerating NAD⁺. Lactic acid fermentation (exercising muscle, RBCs) makes lactate; alcoholic fermentation (yeast) makes ethanol + CO₂. Fermentation yields no additional ATP beyond glycolysis's net 2 — its whole point is recycling NAD⁺.

Pyruvate is transported into the matrix, where the pyruvate dehydrogenase complex decarboxylates it (losing CO₂), oxidizes it (making NADH), and attaches the remaining 2-carbon acetyl group to coenzyme A. Per glucose this happens twice (2 pyruvate → 2 acetyl-CoA, 2 NADH, 2 CO₂). It's irreversible, so acetyl-CoA can't be turned back into glucose — relevant to why fats aren't gluconeogenic.

Also called the Krebs cycle or TCA cycle, it completes the oxidation of glucose's carbons to CO₂ while loading electron carriers. Per acetyl-CoA: 3 NADH, 1 FADH₂, 1 GTP (substrate-level phosphorylation), 2 CO₂. Because each glucose gives two acetyl-CoA, double those numbers per glucose. The cycle's main job isn't ATP — it's producing the NADH and FADH₂ that feed oxidative phosphorylation.

Electrons from NADH (enters at complex I) and FADH₂ (complex II) flow through the chain to progressively higher electron affinity, releasing energy that complexes I, III, and IV use to pump protons out of the matrix. The resulting proton-motive force drives protons back through ATP synthase, which phosphorylates ADP — this is chemiosmosis (Mitchell). Oxygen accepts the spent electrons at complex IV, forming water; without O₂ the whole chain backs up. Roughly 2.5 ATP per NADH and 1.5 per FADH₂. This stage makes the vast majority of ATP.

The bookkeeping per glucose:

The exact total varies (~30–32) because the proton gradient isn't a whole-number machine and the NADH from glycolysis must be shuttled into the mitochondrion. The takeaway: anaerobic = 2 ATP, aerobic ≈ 15× more.

Glycogen is a branched glucose polymer for short-term storage. Insulin promotes glycogenesis (storage); glucagon and epinephrine promote glycogenolysis (release). A key distinction: liver glycogen can release free glucose into the blood, while muscle lacks glucose-6-phosphatase and keeps its glucose for itself.

When glycogen is exhausted, gluconeogenesis keeps blood glucose up for the brain and red blood cells. It uses most glycolytic enzymes in reverse but must bypass the three irreversible steps with separate enzymes: pyruvate carboxylase (pyruvate → oxaloacetate — the committed step, activated by acetyl-CoA) and PEPCK (OAA → PEP) together get around the pyruvate-kinase step; fructose-1,6-bisphosphatase reverses the PFK-1 step; and glucose-6-phosphatase finally frees glucose. Because glucose-6-phosphatase is found in the liver (not muscle), only the liver can release free glucose into the blood. Note acetyl-CoA cannot become glucose (the PDH step is irreversible) — which is why fatty acids are not gluconeogenic.

The pentose phosphate pathway (PPP) runs in the cytoplasm parallel to glycolysis. Its products are NADPH (reducing power for fatty-acid synthesis and for glutathione's antioxidant role) and ribose-5-phosphate (the sugar of nucleotides). Don't expect ATP from it. The oxidative phase is committed by G6PD, the rate-limiting enzyme, which is feedback-inhibited by high NADPH — so the pathway runs only when the cell needs more reducing power.

During hard exercise (or in red blood cells, which have no mitochondria), glycolysis outruns oxygen and lactic acid fermentation makes lactate to regenerate NAD⁺. Rather than waste those carbons, the liver takes up the lactate and runs gluconeogenesis to remake glucose, which re-enters the blood for the muscle to use again. The cycle shifts the metabolic cost: the liver spends ATP to rebuild glucose so the muscle can keep contracting. Note it's a net energy loser (gluconeogenesis costs more ATP than glycolysis yields) — its purpose is to clear lactate and recycle carbon, not to make energy.

Each round of β-oxidation removes a 2-carbon acetyl-CoA and generates one NADH and one FADH₂; the acetyl-CoA then enters the citric acid cycle. Because fatty acids are highly reduced (lots of C–H bonds), they store far more energy per gram than carbohydrate — which is why fat is the body's long-term energy reserve.

When fat breakdown floods the liver with acetyl-CoA faster than the citric acid cycle can use it (low oxaloacetate during fasting), the liver makes ketone bodies (acetoacetate, β-hydroxybutyrate, acetone). These travel to tissues — importantly the brain, which normally relies on glucose — to be reconverted to acetyl-CoA. Excess ketones lower blood pH (ketoacidosis, notably in untreated type 1 diabetes).

Unlike carbs and fats, amino acids carry nitrogen, which must be removed by deamination/transamination and excreted as urea (the urea cycle, in the liver). The leftover carbon skeletons are glucogenic (can make glucose), ketogenic (make ketones/fat), or both.

When fuel is abundant, excess acetyl-CoA is exported from the mitochondrion as citrate (the citrate shuttle) and cleaved back to acetyl-CoA in the cytosol. The committed step is acetyl-CoA carboxylase, which carboxylates acetyl-CoA to malonyl-CoA (this is also the key regulatory/rate-limiting step). Fatty acid synthase then elongates the chain two carbons at a time, consuming NADPH (largely from the pentose phosphate pathway) as reducing power, until it releases the 16-carbon palmitate. Insulin (the fed/storage signal) promotes lipogenesis.

A fatty acid is first activated to fatty acyl-CoA in the cytosol, but that bulky, charged molecule cannot pass the inner mitochondrial membrane on its own. CPT-I (on the outer membrane) swaps the CoA for carnitine, a transporter carries the acyl-carnitine across the inner membrane, and CPT-II (matrix side) swaps carnitine back for CoA — regenerating fatty acyl-CoA inside the matrix, where β-oxidation runs. This shuttle is the committed, rate-limiting entry step for fat burning and the main regulatory checkpoint; malonyl-CoA (a fat-synthesis signal) inhibits CPT-I, preventing simultaneous fat synthesis and breakdown.

After a meal, insulin (from pancreatic β-cells) lowers blood glucose by driving uptake into cells and storage as glycogen and fat. During fasting, glucagon (from α-cells) raises blood glucose by breaking down glycogen and running gluconeogenesis. Epinephrine reinforces the glucagon-type "mobilize" signal under stress. This insulin/glucagon balance is the master switch between the fed (anabolic) and fasting (catabolic) states.

The body shifts fuel sources over time without food: first blood glucose, then liver glycogen (hours), then gluconeogenesis from amino acids and glycerol, and in prolonged starvation a shift to fat and ketone bodies so the brain is fueled and muscle protein is spared. Recognizing which fuel dominates at each stage is a common passage theme.

F2,6BP is a regulatory molecule (not a glycolytic intermediate) made by the enzyme PFK-2 from fructose-6-phosphate. Insulin (high blood glucose) activates PFK-2 → F2,6BP rises → PFK-1 is stimulated and glycolysis speeds up. Glucagon (fasting) triggers phosphorylation that shuts PFK-2 off and instead activates its phosphatase activity, so F2,6BP falls → glycolysis slows and gluconeogenesis is favored. F2,6BP is therefore the molecular link that turns the whole-body insulin/glucagon signal into a decision at the rate-limiting step. The full logic: F2,6BP and AMP say "go"; ATP and citrate say "stop."