Part of the cell · Cofactor and vitamin biosynthesis
Manufacturing cofactors and vitamins
Not labelled on the cell picture.
Many enzymes only work while holding a small helper molecule — a vitamin or cofactor. The cell makes all of them itself.
Proteins in the model: 64
Part of the model's 1051 proteins. Each group below is a book group, counted in the working count after the repeats and non-first-cell groups were removed. The proteins are not yet matched gene by gene.
| Group | Proteins |
|---|---|
| THF derivative-related enzyme group | 4 |
| SAM synthesis enzyme group | 4 |
| Methyl transfer and SAM-related | 2 |
| Biotin biosynthesis | 4 |
| Thiamine biosynthesis | 4 |
| One-carbon metabolism | 4 |
| Cobalamin biosynthesis | 30 |
| Cobalamin recycling | 4 |
| Flavin-related biosynthesis | 4 |
| Pantothenate and CoA biosynthesis | 3 |
| Cobalamin reductase | 1 |
Its pathways
- Heme and quinonesatlas pathway12
- Biotin and lipoateatlas pathway7
- NAD and flavinsatlas pathway6
- Thiamine and pyridoxalatlas pathway6
- Folate and pterin chemistryatlas pathway6
- Lipid and cofactor connectionsatlas pathway5
- Coenzyme Aatlas pathway4
- Aspartate-family branchesatlas pathway3
- Amino-acid connectionsatlas pathway2
- Folate-linked carbon transferatlas pathway1
- Serine, glycine and sulfuratlas pathway1
- Folate biosynthesisKEGG map9
- Oxidative phosphorylationKEGG map5
- Thiamine metabolismKEGG map5
- Pantothenate and CoA biosynthesisKEGG map5
- Glycine, serine and threonine metabolismKEGG map4
- Riboflavin metabolismKEGG map4
- Nicotinate and nicotinamide metabolismKEGG map4
- Biotin metabolismKEGG map4
- Cysteine and methionine metabolismKEGG map3
- Porphyrin metabolismKEGG map3
- Pyruvate metabolismKEGG map2
- Not yet placed in a pathwayto sort37
If it fails
Every enzyme that needs that helper goes dead while its own gene stays perfectly intact. One loss disables a scattered set of otherwise working pathways.
Enzymes go dead · 1–2 generations
What it depends on
- Building carbon into moleculesCarbon intermediates supply the molecular skeletons used to synthesize cofactors.Book pp. 498–499
- Making the twenty amino acidsAmino-acid-derived precursors contribute to pathways such as SAM and other cofactor biosynthesis.Book pp. 498–500
- Turning hydrogen into usable energyATP and reducing power drive cofactor synthesis and regeneration.Book pp. 498–499
What it supplies
- Building carbon into moleculesCoA and one-carbon cofactors enable carbon transfer and acetyl-CoA metabolism in the proposed network.Book pp. 498, 546–550
- Turning hydrogen into usable energyFlavin, NAD, and other cofactors participate in electron-transfer reactions.Book pp. 499
- Making DNA and RNA lettersSelected nucleotide reactions require one-carbon or redox cofactors.Book pp. 498–500
- Making the twenty amino acidsCofactors support amino-group transfer, reduction, and other amino acid biosynthetic reactions.Book pp. 498–500
- Building and maintaining the membraneCoA, biotin in selected pathways, and redox cofactors support lipid biosynthesis.Book pp. 498–501
Dependencies are curated from the book at the level of the map’s systems and are not measured protein contacts. See all systems together.
How it is built and controlled
Counts from UniProt annotations of this group’s proteins.
Its place in the control layer
None of this group’s proteins appear in the information, signaling, regulation, machine-signal or assembly lists.
From the control-layer pages. Which genes a regulator controls is mostly inferred from related bacteria, because Aquifex has no genetic system for testing it directly.
Origins
What needs to be explained
How were useful cofactors made, retained and coupled to catalysts before modern biosynthetic enzymes existed?
What needs explaining. Explain how cofactor chemistry, catalyst specificity and cofactor regeneration became compatible before the modern biosynthetic network existed.
Hurdles
- H-COF-1Chemical supplyThe problem. Enzymes depend on about a dozen cofactors (NAD, FAD, coenzyme A, folate, thiamine, pyridoxal phosphate, S-adenosylmethionine, heme and others), each made by its own multi-step pathway.Why it is hard. Only fragments of a few of these molecules have been made under proposed early-Earth conditions; complete cofactors have not.Chemistry before lifeStage 1: Ingredients made under plausible early-Earth conditionsShown: Some cofactor parts, such as nicotinamide, have been made under proposed prebiotic conditions.In the books: 86 open problems on cofactor metabolism ↗
- H-COF-2Compatible conditionsThe problem. Each cofactor must be made, kept intact and used in the same environment.Why it is hard. Several are unstable to heat, light or oxygen; the conditions that make one tend to destroy another.Chemistry before lifeStage 0: Not yet addressed by experimentShown: not yet addressed by experiment.In the books: 86 open problems on cofactor metabolism ↗
- H-COF-3Binding and specificityThe problem. A cofactor works only when held in a specific pocket of its enzyme, which positions it next to the substrate.Why it is hard. Free cofactors are weak and unselective catalysts; their usefulness comes from the protein that binds them.Molecular machinesStage 2: One step shown on its ownShown: Laboratory-selected ribozymes can use a cofactor such as NAD+, shown one step at a time.In the books: 86 open problems on cofactor metabolism ↗
- H-COF-4RecyclingThe problem. Each cofactor cycles between forms (NAD⁺ and NADH, coenzyme A and acyl-CoA, the forms of folate) and must be regenerated after every use.Why it is hard. Regeneration needs other enzymes and a source of electrons or energy; without it the cofactor is used up after one turn.Molecular machinesStage 0: Not yet addressed by experimentShown: not yet addressed by experiment.In the books: 86 open problems on cofactor metabolism ↗
- H-COF-5Mutual dependenceThe problem. The enzymes that make cofactors are themselves proteins that need cofactors.Why it is hard. Cofactor pathways and the enzymes that depend on cofactors require each other, so neither can be present without the other.The integrated cellStage 0: Not yet addressed by experimentShown: not yet addressed by experiment.In the books: 86 open problems on cofactor metabolism ↗
Scope. A modern cofactor pathway need not have been the first route to that molecule. Modern biosynthesis and prebiotic synthesis are different explanatory questions.
Experimental progress. A reconstructed biosynthetic network connects carbon assimilation with amino acid, nucleotide, and cofactor production. This provides a systems view of shared chemical inputs; a reconstruction is not an experimental demonstration of the first cell.
What would strengthen a natural account. Steps shown to work together under plausible early-Earth conditions, without a chemist choosing the reagents, purifying the products or changing conditions between steps, would strengthen a natural account of origins in proportion to what they explain. Loss of a claimed dependency or discovery of functional alternatives would weaken the corresponding design argument. Gaps in the record do not supply a numerical likelihood for either explanation.
Observations. Cofactor production supports enzymes whose chemistry requires more than a protein chain. Precursor and regeneration pathways connect cofactor supply to metabolism.
Hallmarks that apply.
- H25 Cofactor dependency networks: Cofactor production supports enzymes whose chemistry requires more than a protein chain.
- H24 Metabolic integration: Precursor and regeneration pathways connect cofactor supply to metabolism.
- H27 Material selection: Specific catalysts assemble the required cofactor structures from suitable precursors.
The author’s conclusion. The coordinated features give the author a positive reason to consider design within the wider cellular architecture. For this local system alone, they do not establish that design is uniquely the best historical explanation. The conservative inference is that the system contributes to a cumulative design case, with its weight conditional on the comparative evidence and on how much plausible natural pathways explain.
From the book article Cofactor Metabolism, with its scientific references.
How it was discovered
- 1912Casimir Funk proposes the term “vitamine” for dietary factors needed in small amounts.Funk, Journal of State Medicine 20:341–368 (1912)
- 1932Warburg and Christian describe the “yellow enzyme”, the first flavoprotein.Warburg & Christian, Biochemische Zeitschrift 254:438–458 (1932)
- 1947Lipmann and colleagues identify coenzyme A, the carrier of acetyl groups (Nobel Prize 1953).Lipmann et al., Journal of Biological Chemistry 167:869–870 (1947)
- 1956Dorothy Hodgkin solves the structure of vitamin B12 by X-ray crystallography (Nobel Prize 1964).Hodgkin et al., Nature 178:64–66 (1956)
- 1972Woodward and Eschenmoser complete the laboratory synthesis of vitamin B12, after about a decade of work by about a hundred chemists.Eschenmoser & Wintner, Science 196:1410–1420 (1977)
- 1976Harold White proposes that nucleotide-based cofactors are relics of an earlier, RNA-based stage of metabolism.White, Journal of Molecular Evolution 7:101–104 (1976)
Each hurdle above is sorted by kind and by how far experiments have got (see “How hurdles are sorted” at the top).
All parts of the cell side by side: origins hub. The book articles:
- Cofactor Metabolism: system page · full description · origins