81 - Cellular Resp

Citric acid cycle alternate names

The citric acid cycle is also called the **tricarboxylic acid (TCA) cycle** and the **Krebs cycle**, named after Hans Krebs who discovered it in 1937

Why the citric acid cycle is called a “cycle”

It begins with **oxaloacetate** and ends with **regeneration of oxaloacetate**, allowing continuous operation

What molecule enters the citric acid cycle

**Acetyl-CoA**, derived from pyruvate, fatty acids, or amino acids

Location of the citric acid cycle

The **mitochondrial matrix**

Primary purpose of the citric acid cycle

To **oxidize acetyl-CoA** and generate **reducing equivalents (NADH, FADH₂)** and **GTP**, which support ATP production

What happens to acetyl-CoA carbons in the cycle

They are **oxidized to CO₂**, which is released as metabolic waste

Net products per turn of the citric acid cycle

**3 NADH, 1 FADH₂, 1 GTP (ATP equivalent), and 2 CO₂**

Net products per glucose from the citric acid cycle

Since glucose yields **2 acetyl-CoA**, the cycle produces **6 NADH, 2 FADH₂, 2 GTP, and 4 CO₂ per glucose**

What type of molecules NADH and FADH₂ are

**Reducing equivalents** that carry high-energy electrons to the electron transport chain

Purpose of generating NADH and FADH₂

To supply electrons to the **electron transport chain**, which generates most ATP

Why CO₂ is produced during the cycle

CO₂ is released during **oxidation reactions** as carbons are removed from intermediates

What happens to CO₂ produced in metabolism

It diffuses into the bloodstream and is **exhaled through the lungs**

Role of coenzyme A in metabolism

Coenzyme A acts as a **carrier of acyl groups** and is **recycled** after reactions

Why NAD⁺ availability is important for the cycle

NAD⁺ must be available to **accept electrons** so oxidation reactions can continue

What happens if NADH accumulates

Excess NADH **inhibits key dehydrogenase enzymes**, slowing the cycle

Three main ways the citric acid cycle is regulated

**Substrate availability**, **product inhibition**, and **allosteric regulation**

Importance of substrate availability

The cycle requires both **oxaloacetate** and **acetyl-CoA** in a **1:1 ratio**

Why NAD⁺ is considered a substrate regulator

Without NAD⁺, oxidation reactions cannot proceed

Example of product inhibition in the cycle

**NADH accumulation inhibits dehydrogenases**

Role of ATP in regulation

**ATP is a negative allosteric regulator**, signaling high energy availability

Role of ADP in regulation

**ADP is a positive allosteric regulator**, signaling low energy and increasing cycle activity

Role of calcium ions in regulation

**Calcium is a positive allosteric regulator** that stimulates key enzymes during muscle contraction

Why calcium stimulates the citric acid cycle in muscle

Calcium release during contraction signals **increased energy demand**, activating fuel oxidation

What cellular conditions stimulate the citric acid cycle

**Low ATP, high ADP, high Ca²⁺**

What cellular conditions inhibit the citric acid cycle

**High ATP, high NADH**

Major indicator of cellular energy status

The **ATP/ADP ratio**

Major indicator of cellular redox state

The **NADH/NAD⁺ ratio**

Meaning of feedback inhibition in metabolism

**Products inhibit earlier enzymes**, controlling pathway flux

Why only some enzymes are regulated

Controlling a few key steps is sufficient to regulate the entire pathway

Similarity between glycolysis and citric acid cycle regulation

Both respond to **energy status** and **redox state**

Definition of amphibolic pathway

A pathway that functions in **both catabolism and anabolism**

Why the citric acid cycle is considered catabolic

It **breaks down acetyl-CoA** to generate energy carriers

Why the citric acid cycle is considered anabolic

It provides **intermediates used in biosynthesis**

Examples of anabolic uses of citric acid cycle intermediates

Citrate → fatty acids and steroids; Succinyl-CoA → heme synthesis; α-Ketoglutarate → amino acids; Oxaloacetate → amino acids and nucleotides

Why intermediates cannot be removed indefinitely

Removing intermediates without replacement would **stop the cycle**

Definition of anaplerosis

The **replenishment of citric acid cycle intermediates**

Most important anaplerotic reaction in animals

**Conversion of pyruvate to oxaloacetate**

Enzyme that catalyzes pyruvate to oxaloacetate conversion

**Pyruvate carboxylase**

Why oxaloacetate replenishment is critical

Oxaloacetate must be present to **combine with acetyl-CoA** and begin the cycle

What happens if oxaloacetate is depleted

The cycle **slows or stops**, limiting energy production

Purpose of coordinating PDH and pyruvate carboxylase

To maintain a **1:1 ratio of oxaloacetate to acetyl-CoA**

What happens when acetyl-CoA levels are high

Excess acetyl-CoA **inhibits pyruvate dehydrogenase (PDH)**

Where pyruvate is directed when PDH is inhibited

Pyruvate is converted to **oxaloacetate via pyruvate carboxylase**

Why this coordination is important

Ensures **sufficient oxaloacetate** to support the citric acid cycle

How carbohydrates fuel the citric acid cycle

Glucose → pyruvate → acetyl-CoA → citric acid cycle

How fats fuel the citric acid cycle

Fatty acids → β-oxidation → acetyl-CoA → citric acid cycle

How proteins fuel the citric acid cycle

Amino acids are converted into **citric acid cycle intermediates**

Examples of amino acids feeding into the cycle

Alanine, aspartate, and glutamate can be converted into cycle intermediates

Why the citric acid cycle is central to metabolism

It integrates metabolism of **carbohydrates, fats, and proteins**

What happens to pyruvate in mitochondria

Pyruvate is converted to **acetyl-CoA and CO₂**

Total reducing equivalents produced from oxidation of pyruvate

**4 NADH, 1 FADH₂, and 1 GTP**

Why oxidation of pyruvate is tightly regulated

It determines how much fuel enters the citric acid cycle

Main determinant of flux through pyruvate oxidation and CAC

**Energy status of the cell**

Why the citric acid cycle depends on oxaloacetate availability

Without oxaloacetate, acetyl-CoA **cannot enter the cycle**

Why NADH inhibits the citric acid cycle

High NADH signals **sufficient energy**, slowing further oxidation

Why ADP activates the citric acid cycle

High ADP signals **low energy**, increasing ATP production

Why calcium activates the citric acid cycle in muscle

Calcium release signals **energy demand during contraction**

Why the citric acid cycle is amphibolic

It functions in **energy production and biosynthesis**

Why anaplerotic reactions are essential

They **replenish intermediates** removed for biosynthesis

Why two turns of the cycle occur per glucose

One glucose produces **two acetyl-CoA molecules**

Why NADH and FADH₂ are more important than GTP production

They generate **most ATP indirectly via oxidative phosphorylation**

Why metabolism slows when ATP levels are high

High ATP **inhibits key regulatory enzymes**

Why excess acetyl-CoA diverts pyruvate to oxaloacetate formation

To **restore oxaloacetate levels** and support cycle continuation