Amino Acids Lecture Notes

Amino Acids and Metabolism

Lecture Introduction

The lecturer acknowledges potential disjointedness in this lecture's flow compared to previous ones.
Content has been cut down to avoid overwhelming students.
Focus on understanding the processes discussed – they are crucial for learning.

Review of Previous Lecture

Digestion of proteins begins in the stomach with pepsin, which cleaves peptide bonds.
Hydrochloric acid in the stomach denatures proteins, making peptide bonds accessible.
Proteases in the small intestine further break down proteins into single amino acids, dipeptides, or tripeptides for absorption.

Ozempic Example (Semaglutide)

Ozempic is a modified peptide drug administered via subcutaneous injection to avoid degradation in the stomach.
An oral version of Ozempic exists but is less effective because semaglutide (the active ingredient) degrades in the stomach and small intestine.
Oral Ozempic requires a much higher dose (e.g., 14 mg daily vs. 0.25 mg weekly injection) to compensate for degradation.
Clinical trials show the injectable form is significantly more effective.

Amino Acid Metabolism

Amino acids are used to:
- Synthesize new proteins.
- Produce glucose and energy.
- Synthesize other molecules (e.g., glutamate as a signaling molecule, tyrosine to make adrenaline).
Old proteins are tagged with ubiquitin for destruction by proteases like the 20S protease.

Essential vs. Non-Essential Amino Acids

There are 20 amino acids.
The body can synthesize about 10 of them (non-essential).
The remaining amino acids must be obtained from the diet (essential), mainly from meat, eggs, beans, and nuts.

Glucogenic vs. Ketogenic Amino Acids

Glucogenic amino acids can be converted into pyruvate, which can then be used to make glucose.
Ketogenic amino acids can be broken down into ketone bodies (e.g., acetone).
Some amino acids can be both glucogenic and ketogenic.
Acetone is a ketone body. Nail polish remover contains acetone and ethyl acetate.

Core Metabolic Pathways: Transamination

Transamination involves swapping an amine group for a carbonyl group.
This process is essential for synthesizing non-essential amino acids and obtaining nitrogen for other processes, such as DNA synthesis.

Transamination Process

Glutamate is a key reactant, converting to alpha-ketoglutarate by removing the amine group.
A keto acid receives the amine group, becoming an amino acid.
Enzymes involved include alanine aminotransferase and aspartate aminotransferase.
Pyridoxal phosphate (PLP) is an important cofactor in transamination.
The reaction is reversible, providing metabolic flexibility.

Nitrogen Source and the Nitrogen Cycle

Humans primarily obtain nitrogen from amino acids in their diet.
There is no nitrogen storage in the human body; a continuous supply is needed.
Atmospheric nitrogen (about 70%) is converted into ammonia by bacteria and fungi (nitrogen fixation).
This ammonia is then used to create amino acids.
Fritz Haber developed the Haber process for synthesizing ammonia, crucial for fertilizer production during the industrial revolution. He also created mustard gas and enabled the Germans in World War 1 to do a lot of chemical warfare, which raised calls that he should be stripped of his Nobel Prize afterwards because of that.

Importance of Bacteria

Bacteria and fungi convert atmospheric nitrogen into ammonia, which is essential for synthesizing amino acids, nucleotides, porphyrins (used in enzymes like hemoglobin), proteins, DNA, complex polysaccharides, and phospholipids.

Nitrogen Balance and Waste

Humans must consume enough nitrogen because they can't store it.
Adults need about 8 grams of nitrogen per day, equivalent to at least 52 grams of protein.
Insufficient nitrogen intake leads to the breakdown of proteins (muscle) to obtain nitrogen.
Excess nitrogen is converted into urea in the liver and excreted in urine.
Urea production requires ATP and involves carbon dioxide, amine, and aspartate.
The enzyme alanine aminotransferase and aspartate aminotransferase, is involved.
The smell of urine is due to ammonia, not urea. Strong-smelling urine indicates high ammonia content, which is not good.
The yellow color of urine is due to bilirubin, a breakdown product of hemoglobin.

Glutamate and Glutamine

Glutamate donates its amine group, it can turn into glutamine by replacing one of the oxygens.
Glutamine is synthesized from glutamate in most tissues and the bloodstream, requiring ATP.
In the liver, glutamine is converted back into glutamate, releasing ammonia.
In muscles, amino acids are converted into glutamate via transamination.
Glutamate and pyruvate can be converted into alanine, which is part of a cycle for glucose production.

Ketone Bodies

Ketone bodies are produced when amino acids are stripped of their amine groups leaving: acetoacetate, beta-hydroxybutyrate, and acetone are the three main ketone bodies.
They are used as an alternative energy source when glucose is insufficient.
Ketone bodies are converted into acetyl coenzyme A to enter the Krebs cycle.

Amino Acid Synthesis

Plants can synthesize all 20 amino acids.
Humans can only synthesize some amino acids.
Glycolysis, the Krebs cycle, and the pentose phosphate pathway contribute intermediates for amino acid biosynthesis.
Alpha-ketoglutarate is used to make glutamate, which can then be used to make amine-rich amino acids (glutamine, proline and arginine).
Oxaloacetate is used to make aspartate, which can then be used to make asparagine, methionine, threonine and lysine.
Pyruvate is used to make hydrophobic amino acids (alanine, valine, leucine and isoleucine).

Regulation of Amino Acid Biosynthesis

Regulation occurs via feedback inhibition.
The final product of a pathway inhibits the enzyme that initiates the pathway.
For processes involving one or two enzymes, the product inhibits those enzymes.

Amino Acid Metabolic Disorders

These are often inherited disorders caused by genetic mutations.

Phenylketonuria (PKU)

Caused by a deficiency in phenylalanine hydroxylase that leads to the buildup of phenylalanine.
Excessive phenylalanine crosses the blood-brain barrier and causes brain damage and developmental disorders.
Symptoms include seizures and a musty odor in urine.
Management involves a lifetime diet of low protein.

Alkaptonuria

Caused by a deficiency in an enzyme that breaks down homogentisic acid (produced from phenylalanine and tyrosine degradation).
Symptoms include dark spots on the body, stiff cartilage, arthritis, and dark-colored urine.
Treatment involves a low-protein diet.

Maple Syrup Urine Disease

Caused by a deficiency in a complex of enzymes that process leucine, isoleucine, and valine.
It causes a buildup of these amino acids in the blood.
The disease is characterized by sweet-smelling urine.
Other symptoms include a lack of energy, vomiting, seizures and coma.
Treatment includes a lifetime diet of low protein and thiamine supplementation.

Clinical Trials and Drug Development

Drug development takes about 15 years and costs between $1 billion and $5 billion.
99% of drugs fail during clinical trials.
Pharmaceutical companies undertake a cost-benefit analysis before developing a drug.
Orphan drug designation is present when no one wants to pick it up due to market sizes
Orphan drugs are those that affect rare populations.
Monoclonal antibody drugs are expensive due to the cost of developing them and the small patient populations they treat ($10,000 to $100,000 per dose).

Amino Acids and Cancer Treatment

Cancer cells have high metabolism and nutrient uptake.
Chemotherapy drugs target fast-growing cells, including cancer cells, bone marrow, gastrointestinal lining, hair follicles, and fetuses.
Side effects of chemotherapy are due to the impact on healthy, fast-growing cells.

Targeting Amino Acid Metabolism in Cancer

Blocking nutrient uptake can halt cancer growth.
Some breast cancers are estrogen-positive and treated by blocking estrogen receptors.
Cancers need a lot of sugar (glucose) and amino acids to grow.
Blocking glucose receptors on cancer cells and reducing glucose intake are potential strategies.

Targeting Enzymes

Plants and animals have similar processes but often have slightly different versions of the proteins and therefore, can be specifically targeted by toxins such as glyphosate.
Glyphosate is an herbicide that blocks an enzyme in plants involved in amino acid metabolism.

Review Questions and High Level Analysis

What is excess ammonia converted to in the body for excretion in urine? (Answer: Urea)
What proteins are involved in transamination, what cofactors are involved, and what products are made? (Answer: Alanine transferase, PLP, amino acid, and alpha-ketoglutarate)
If a patient had a condition where they were not able to metabolize one or more amino acids, what would be the potential treatment for that person and why? (Answer: Eat less protein to reduce the buildup of unmetabolized amino acids)