Primer · Nutritional Biochemistry
How glucose, fat, and protein all become ATP — and how the body runs the same machinery in reverse to build fat, build glucose, and make ketones — mapped against the B vitamins that make every step run.
Three fuels — glucose, fat, and, when needed, protein — funnel down to one molecule, acetyl‑CoA, and one hub, the Krebs cycle. This paper is built around flow more than mechanism: the diagrams carry the argument, and the text is there to name what the arrows mean. A small, fixed set of B‑vitamin‑derived coenzymes runs the whole system — TPP (B1), FAD (B2), NAD+ (B3), CoA (B5), PLP (B6), and biotin (B7) — and the same handful of molecules (pyruvate, acetyl-CoA, citrate) keep reappearing as the junctions where the body decides which way to run the traffic: toward ATP, or toward building something.
The pathway facts here are standard biochemistry (Lehninger, Harper's Illustrated Biochemistry) and not in dispute. Organizing the pathways around which B vitamin does which specific job follows the teaching style of Chris Masterjohn.
Three fuels in, four ways the traffic can reverse, six parts
Follow the arrows first. The names are secondary.
THE BIG PICTURE
Ten steps in the cytosol, no oxygen needed: five that spend ATP priming glucose for cleavage, then five — run twice, once per 3-carbon half — that repay it with a profit. Only one step is a redox reaction; it's the only place niacin is used directly in these ten steps.
Net per glucose: 2 ATP, 2 NADH, and 2 pyruvate. The investment phase (hexokinase, PFK-1) spends 2 ATP; the payoff phase runs twice — once per triose — repaying that loan and netting 2 ATP plus 2 NADH.
Pyruvate isn't a Krebs cycle intermediate. One more step, pyruvate dehydrogenase (PDH), decarboxylates it to acetyl-CoA first — and that single enzyme pulls in five cofactors at once, more than any other step in this paper.
Same five cofactors, same reaction template, repeat almost exactly at α-ketoglutarate dehydrogenase inside the Krebs cycle (III.2) — thiamine status can throttle carbon flow into the cycle from two separate directions.
Fat is dismantled in the mitochondrial matrix by a four-step loop that repeats, not a line that runs once. A C16 chain like palmitate spins through it seven times, releasing eight acetyl-CoA and reducing seven FAD and seven NAD+ along the way.
Per turn: 1 FADH2, 1 NADH, 1 acetyl-CoA. A C16 chain (palmitate) spins through seven turns, releasing eight acetyl-CoA for the Krebs cycle below.
Every acetyl-CoA — from glucose or from fat — enters the same eight-step wheel. Oxaloacetate regenerates at the end of each turn, so the cycle never runs out of a place to put the next acetyl group.
Per turn: 3 NADH, 1 FADH2, 1 GTP, 2 CO2. The two decarboxylation steps and the succinate dehydrogenase step double as a direct entry point into the electron transport chain.
α-Ketoglutarate dehydrogenase is structurally almost identical to pyruvate dehydrogenase (I.2) and needs the same five cofactors — B1, lipoic acid, B2, B3, B5 — a second checkpoint where thiamine status alone can throttle the cycle. Succinate dehydrogenase is the only Krebs cycle enzyme embedded in the inner mitochondrial membrane: it's also Complex II of the electron transport chain, so this one step belongs to both pathways at once.
Amino acids — from dietary protein, or from muscle during fasting or very-low-carb intake — can be stripped of their nitrogen and fed into the same pathways as carbon skeletons. Every one of the twenty shares the same entry mechanism.
An aminotransferase (ALT and AST are the two on a standard liver panel) transfers the amino acid's –NH₂ group onto α-ketoglutarate. The amino acid becomes a keto acid; α-ketoglutarate becomes glutamate. Same swap, all twenty times, always on the same cofactor.
Glutamate's amine is then released as free ammonia (glutamate dehydrogenase, NAD+/NADP+) and disposed of via the liver's urea cycle — an ATP-costly system separate from the ATP-generating pathways above.
The keto acid lands at one of six points already drawn above: pyruvate, acetyl-CoA, or a Krebs cycle intermediate. Land at pyruvate or a Krebs intermediate and the carbon can run back to glucose (glucogenic, via gluconeogenesis). Leucine and lysine land only at acetyl-CoA, which can't run backward — purely ketogenic. A few amino acids split across two doors and count as both.
Every arrow above is PLP-dependent (B6). Alanine, serine, glycine, and cysteine feed pyruvate; glutamate, glutamine, histidine, proline, and arginine feed α-ketoglutarate; aspartate and asparagine feed oxaloacetate; isoleucine, methionine, valine, and threonine feed succinyl-CoA; phenylalanine and tyrosine feed fumarate. Leucine and lysine are the only two amino acids that are purely ketogenic — every other amino acid can, at least partly, run back to glucose.
Everything above runs toward ATP. The same junction molecules — citrate, pyruvate, glucose-6-phosphate, acetyl-CoA — also sit at the start of four branches that run the traffic somewhere else: building fat, building glucose, building nucleotide precursors, or building an alternative fuel for when glucose is scarce.
When acetyl-CoA and ATP are both abundant, citrate backs up and is exported out of the mitochondria instead of continuing around the Krebs wheel.
The rate-limiting step, acetyl-CoA carboxylase, needs biotin (B7) — the same vitamin that runs pyruvate carboxylase in gluconeogenesis below.
Liver and kidney rebuild glucose from lactate, alanine, and glycerol. Seven of the ten glycolysis steps just run in reverse; three are one-way, so the body uses different enzymes to get around them.
Sky-colored arrows are the same enzymes as Part I, run backward. Gold arrows are gluconeogenesis-only detours around the three irreversible glycolysis steps — the first needs biotin.
Before glucose-6-phosphate (G6P) commits to glycolysis, some of it can branch off to make NADPH — the electron donor lipogenesis and antioxidant defenses run on — and ribose-5-phosphate for nucleotide synthesis.
2 NADPH per G6P, spent above in lipogenesis (V.1) and on glutathione regeneration. The pathway's non-oxidative half (not shown) can run in reverse and needs TPP (B1) — the same cofactor as pyruvate dehydrogenase.
Fasting or very-low-carb intake drops oxaloacetate (it's pulled toward gluconeogenesis), so the liver's mitochondria can't condense all the acetyl-CoA β-oxidation is producing. The surplus becomes ketone bodies instead.
β-Hydroxybutyrate travels to other tissues — brain included — as an alternative fuel to glucose. Acetone is mostly exhaled, which is where the fruity breath in ketosis or diabetic ketoacidosis comes from.
Each B vitamin converts into an active coenzyme before it can do anything. A deficiency doesn't cause a generic drop in “energy” — it stalls a specific, nameable step. The individual nutrient pages carry deficiency signs, intake targets, and food sources for each.
| Vitamin | Coenzyme | Acts in | Role |
|---|---|---|---|
| B1 · Thiamine | TPP | I, III, V | Pyruvate dehydrogenase (I.2) and α-ketoglutarate dehydrogenase (III.2) — both decarboxylation steps — plus the reversible half of the pentose phosphate pathway (V.3). |
| B2 · Riboflavin | FAD / FMN | II, III | Electron acceptor for acyl-CoA dehydrogenase in every turn of β-oxidation and for succinate dehydrogenase in the Krebs cycle, which feeds those electrons directly into Complex II. |
| B3 · Niacin | NAD+ / NADP+ | I–V | NAD+ runs GAPDH, β-oxidation, and three Krebs steps. Its cousin NADP+ is what the pentose phosphate pathway (V.3) reduces to NADPH — the electron donor lipogenesis (V.1) spends. |
| B5 · Pantothenic acid | Coenzyme A | I–V | CoA is the handle every acyl group is carried by — acetyl-CoA, malonyl-CoA, HMG-CoA — through β-oxidation, the Krebs cycle, lipogenesis, and ketogenesis alike. |
| B6 · Pyridoxine | PLP | IV | PLP runs every transamination in Part IV — swapping an amine for a keto group and handing twenty carbon skeletons into six points on the pathways above. |
| B7 · Biotin | Carboxylase prosthetic group | III, V | Pyruvate carboxylase refills the Krebs cycle (III) and starts gluconeogenesis (V.2); acetyl-CoA carboxylase is the rate-limiting step of lipogenesis (V.1). Same vitamin, opposite directions. |
TPP, CoA, FAD, and NAD+/NADP+ do almost all the direct chemistry. B6 and biotin sit at the branch points instead — B6 decides what protein becomes, biotin decides whether pyruvate builds glucose or acetyl-CoA builds fat. See Metabolic Health for how this fits into mitochondrial capacity and insulin sensitivity.