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Publisher Contact:
- Editorial Address: Macmillan & Co., Ltd., St. Martin's Street, London, W.C.
- Telegraphic Address: PHUSIS, LESQUARE, LONDON
- Telephone Number: WHITEHALL 8831
- Date: 14th June 1937
Citation:
- Krebs, H. A., & Johnson, W. A. (1937). The role of citric acid in intermediate metabolism in animal tissues. Enzymologia, 4 (Dec), 148–156.
Note from the Editor of Nature:
- Acknowledgment of receipt of letter from Mr. H. A. Krebs, expressing regret about publication delays.
- Will hold the letter until congestion is relieved for possible publication.

Basic Components:
- Key Inputs:
- Acetyl CoA from glucose, fatty acids, or amino acids
- Outputs:
- 2 CO₂
- High energy electrons captured as NADH and FADH₂
- 1 ATP generated directly from the cycle
Energy Production:
- Cycle harvests high-energy electrons that contribute to the formation of 9 ATP during oxidative phosphorylation.

Enzyme: Citrate synthase
Process: Synthetic reaction that does not utilize ATP.
Mechanism:
- Thioester hydrolysis of CoA drives the reaction.
- Acetyl CoA binds after oxaloacetate does, creating the active site that produces citryl CoA and then converts it into citrate.
Chemical Reaction:
- $ext{Acetyl CoA} + ext{Oxaloacetate} + ext{H}_2 ext{O} ightarrow ext{Citrate} + ext{CoA} + ext{H}^+$

Enzyme: Aconitase
Description:
- Hydroxyl group movement from the central carbon to a position closer to a terminal carbon.
- Involves dehydration and hydration reactions to prepare the molecule for oxidative decarboxylation.
Chemical Reaction:
- $ext{Citrate} ightarrow ext{cis-Aconitate} + ext{H}_2 ext{O}$
- $ext{cis-Aconitate} + ext{H}_2 ext{O} ightarrow ext{Isocitrate}$

Enzyme: Isocitrate dehydrogenase
Process:
- Isocitrate is converted to alpha-ketoglutarate by removing an electron from the -OH group, converting it to a carbonyl (=O).
- This electron is captured by NAD⁺ forming NADH (first one).
- After the conversion, oxalosuccinate, an unstable intermediate, releases CO₂.
Chemical Reaction:
- $ext{Isocitrate} + ext{NAD}^+ ightarrow ext{a-Ketoglutarate} + ext{CO}_2 + ext{NADH}$

Enzyme: Alpha-ketoglutarate dehydrogenase complex
Homologous Process: Similar to the pyruvate dehydrogenase complex.
Mechanism:
- Converts alpha-ketoglutarate into succinyl CoA through oxidative decarboxylation involving a complex of three subunits.
- Electrons are captured by NADH (second one), and a high-energy thioester bond is formed.
Chemical Reaction:
- $ext{a-Ketoglutarate} + ext{NAD}^+ + ext{CoA} ightarrow ext{Succinyl CoA} + ext{CO}_2 + ext{NADH}$

Table 19.1 - Citric Acid Cycle Overview
- Each reaction step includes respective enzymes, Gibbs free energy changes (∆G), and types of prosthetic groups involved.
- Reaction Steps and Details:
  - Step 1:
  - Reaction: Acetyl CoA + Oxaloacetate + H₂O → Citrate + CoA + H⁺
  - Enzyme: Citrate synthase
  - ∆G°': -31.4 kJ mol⁻¹ (-7.5 kcal mol⁻¹)
  - Type: a (condensation)
  - Step 2:
  - Rd. Acetyl CoA → L-Malate
  - Comparison: Similar to a phosphorylation by ATP
  - Full Gibbs Free Energy Table is included detailing changes for each step.

Biosynthesis Components:
- Compounds generated in the citric acid cycle not only contribute to energy production but also serve as precursors for various biosynthesis processes.
- Examples of retainable compounds from the cycle include:
  - Pyruvate: Utilized to create glucose and other amino acids.
  - Acetyl CoA: Precursor for fatty acids, sterols.
  - Oxaloacetate: Can convert to aspartate.
  - Succinyl CoA: Precursor for porphyrins (heme, chlorophyll).
  - a-Ketoglutarate: Can be converted into glutamate and other amino acids.
Important Note: These pathways are active when energy requirements are satisfied, highlighting the versatile nature of the cycle in cellular metabolism.