week 6

Chapter 35: Leaks in the Tricarboxylic Acid (TCA) Cycle

Overview of the TCA Cycle

  • The TCA (Tricarboxylic Acid) cycle is categorized as an amphibolic pathway, performing both oxidative and biosynthetic functions.

    • Oxidative functions of the TCA cycle entail complete burning of acetyl-CoA, subsequently generating ATP via oxidative phosphorylation.

    • Many intermediates of the TCA cycle serve as substrates for various biosynthetic pathways, leading to "leaks" in the cycle.

Important Intermediates & Their Fate

  • Citrate leakage:

    • Can exit the mitochondria due to its permeability to mitochondrial membranes.

    • In the cytoplasm, citrate is cleaved by citrate lyase into oxaloacetate (OAA) and acetyl-CoA.

    • The acetyl-CoA is redirected for lipid biosynthesis, particularly fatty acids.

  • Oxaloacetate (OAA) leakage:

    • Utilized for glucose biosynthesis and can leak into pathways forming pyrimidines.

  • Succinyl-CoA:

    • Leaks into the formation of porphyrins, including heme.

  • Other intermediates may leak and be used for protein synthesis.

Anaplerotic Reactions

  • These reactions are critical for replenishing intermediates that are lost or diverted from the TCA cycle, ensuring its continued functionality.

    • A significant anaplerotic reaction includes the carboxylation of pyruvate to form OAA.

Intermediates in Amino Acid Synthesis

  • Two key compounds involved in amino acid synthesis are OAA and α-ketoglutarate (α-KG).

    • In other metabolic pathways, intermediates like 3-phosphoglycerate and pyruvate also contribute to amino acids.

  • Plant and bacterial biosynthesis employs fumarate, succinyl-CoA, acetyl-CoA, and acetoacetyl-CoA, while animals only utilize certain ones.

Implications for TCA Cycle Activity

  • If intermediates leak out and are not replenished, TCA cycle activity drops, leading to inadequate oxidation of acetyl-CoA.

Replenishing the TCA Cycle Intermediates

  • Key Replenishers:

    • Glucose replenishes intermediates to maintain the cycle functionality; pyruvate, derived from glucose, can regenerate OAA through pyruvate carboxylase.

    • Proteins also contribute amino acids that can be converted into TCA cycle intermediates.

    • The facility for amino acids to be transaminated or deaminated allows for their conversion to intermediates.

Key Amino Acid Transformations

  • Transamination: several nonessential amino acids can convert back and forth with their corresponding α-ketoacids, e.g.:

    • Alanine / Pyruvate

    • Aspartate / OAA

    • Glutamate / α-KG

  • For net conversions to TCA intermediates, oxidative deamination of glutamate is crucial to release NH₃, which is then typically converted to urea in the liver.

Special Considerations for Ruminants

  • Propionate acts as a source for replenishing TCA intermediates by forming succinyl-CoA. This is significant for ruminants that depend on gluconeogenesis for glucose from various sources including propionate.

  • The conversion mechanisms to succinyl-CoA require vitamins B (pantothenate, biotin, cobalamin).

Summary of Connections and Utilization in Organism Metabolism

  • The interrelation between TCA cycle and gluconeogenesis is paramount; OAA and support from acetyl-CoA are essential for efficient metabolic processes.

  • Metal Affinities: Porphyrins, synthesized from succinyl-CoA in certain tissues, exhibit unique bindings, most notably to iron to form heme.

Division of TCA Cycle Functions

  • The TCA cycle can be conceptually separated into two main steps:

    1. From acetyl-CoA and OAA to α-KG

    2. From α-KG or succinyl-CoA to malate and/or OAA.

  • This division provides insight on how intermediates can be inserted and withdrawn without disrupting energy production.

Connections to Oxidative Phosphorylation

  • The TCA cycle is linked to aerobic respiration processes, implicating its importance in utilizing NADH and FADH₂ for ATP generation via the electron transport chain (ETC).

  • ETC Overview:

    • Major consumer of O₂ in mammalian cells.

    • NADH and FADH₂ electrons transfer through protein complexes.

    • Mobile carriers like Coenzyme Q and Cytochrome c play essential roles.

Key Objectives

  • Discuss the amphibolic nature of the TCA cycle and the associated anaplerotic reactions.

  • Illustrate the significance of pyrimidine and porphyrin synthesis as leaks in the cycle.

  • Elucidate how the Asp/OAA pool is challenged during hepatic gluconeogenesis.

  • Identify how glucose and proteins assist in rejuvenating the cycle during muscle excitatory States.

  • Convey the reasons for the separation of certain mitochondrial enzymes in the cytoplasm.

Questions & Answers

  1. Which intermediate leaks to enter porphyrin biosynthesis? Answer: e. Succinyl-CoA

  2. Which intermediate leaks to enter pyrimidine biosynthesis? Answer: a. Oxaloacetate

  3. Which amino acid can undergo deamination and transamination? Answer: a. Glu

  4. Which is an anaplerotic reaction for the TCA cycle? Answer: c. Pyruvate –> Oxaloacetate

  5. Which does NOT replenish TCA cycle intermediates? Answer: d. Vitamin B12

  6. Which is impermeable to mitochondrial membranes? Answer: d. OAA

  7. Which carbon removal doesn't occur for TCA cycle to form other compounds? Answer: e. Guanine