Amino Acids : Metabolism Pathway
Amino Acids & Protein Digestion/Absorption
Amino acids are the building blocks of proteins and play a central role in numerous metabolic pathways. Unlike carbohydrates and fats, the body has no dedicated storage form for amino acids. Instead, there's a dynamic "amino acid pool" that constantly receives and donates amino acids for various purposes.
The General Fates of Amino Acids
Once available in the body (either from diet, protein turnover, or de novo synthesis), amino acids follow several major metabolic pathways:
- Protein Synthesis (Anabolism): This is the primary and most vital role of amino acids. They are precisely assembled into new proteins (structural, enzymatic, hormonal, transport, etc.) within cells according to genetic instructions. This process is continuous, as proteins have finite lifespans and are constantly being synthesized and degraded (protein turnover).
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Synthesis of Non-Protein Nitrogenous Compounds: Amino acids are precursors for a vast array of other essential nitrogen-containing molecules that are not proteins. These include:
- Neurotransmitters: e.g., dopamine, serotonin, GABA
- Hormones: e.g., thyroid hormones, adrenaline (epinephrine)
- Nucleotides: Components of DNA and RNA
- Heme: The iron-containing component of hemoglobin
- Creatine: Involved in energy storage in muscles
- Polyamines: Involved in cell growth and differentiation
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Catabolism (Breakdown for Energy or Other Metabolites): When amino acids are in excess, or when energy stores (carbohydrates and fats) are insufficient, amino acids can be catabolized. This involves:
- Removal of the Amino Group: The nitrogen-containing amino group is removed (primarily as ammonia), which is then typically converted to urea for excretion.
- Metabolism of the Carbon Skeleton: The remaining carbon skeleton (α-keto acid) can be:
- Oxidized directly for energy (e.g., to Acetyl-CoA, TCA cycle intermediates).
- Converted into glucose (via gluconeogenesis).
- Converted into ketone bodies (via ketogenesis).
- Converted into fatty acids for storage.
Protein Digestion and Absorption
The body acquires amino acids primarily from the diet through the breakdown of ingested proteins. This process occurs in several stages:
In the Stomach:
- Denaturation: Dietary proteins first encounter the highly acidic environment of the stomach (pH 1.5-3.5) due to hydrochloric acid (HCl) secreted by parietal cells. This low pH causes proteins to denature, unfolding their complex three-dimensional structures and making them more accessible to enzymatic degradation.
- Pepsin Activity: Chief cells in the stomach secrete pepsinogen, a zymogen (inactive enzyme precursor). HCl cleaves pepsinogen to its active form, pepsin. Pepsin is an endopeptidase, meaning it hydrolyzes peptide bonds within the protein chain, preferentially cleaving bonds involving aromatic amino acids. This produces a mixture of smaller polypeptides and some oligopeptides.
In the Small Intestine (Duodenum):
- Neutralization: As the acidic chyme (partially digested food) moves from the stomach into the duodenum, its acidity stimulates the release of secretin and cholecystokinin (CCK). Secretin stimulates the pancreas to release bicarbonate, which neutralizes the stomach acid, raising the pH to around 7. This optimal pH is crucial for the activity of pancreatic proteases.
- Pancreatic Proteases: The pancreas secretes a cocktail of zymogens, including:
- Trypsinogen: Activated by enteropeptidase (also called enterokinase), an enzyme on the intestinal brush border, to form trypsin. Trypsin is a key enzyme because it then activates all other pancreatic zymogens.
- Chymotrypsinogen: Activated by trypsin to form chymotrypsin.
- Proelastase: Activated by trypsin to form elastase.
- Procarboxypeptidases A and B: Activated by trypsin to form carboxypeptidases A and B.
- Endopeptidases (Trypsin, Chymotrypsin, Elastase): These enzymes continue to hydrolyze internal peptide bonds within the polypeptides, breaking them down into smaller oligopeptides and tri- and di-peptides. Trypsin preferentially cleaves at basic amino acids (lysine, arginine), while chymotrypsin prefers aromatic amino acids (phenylalanine, tyrosine, tryptophan).
- Exopeptidases (Carboxypeptidases A and B): These enzymes remove amino acids one by one from the carboxyl (C-terminal) end of the polypeptide chains, producing free amino acids.
At the Intestinal Brush Border and Within Enterocytes:
- Brush Border Peptidases: The surface of the enterocytes (intestinal absorptive cells) contains various aminopeptidases and dipeptidases. Aminopeptidases cleave amino acids from the amino (N-terminal) end of oligopeptides. Dipeptidases and tripeptidases hydrolyze di- and tripeptides into free amino acids.
- Absorption into Enterocytes:
- Free Amino Acids: Absorbed by specific Na⁺-dependent co-transporters on the apical membrane (lumen side) of enterocytes. Different transporters exist for different classes of amino acids (e.g., neutral, basic, acidic).
- Di- and Tri-peptides: A significant portion of di- and tri-peptides are absorbed intact into the enterocytes via a separate proton-dependent cotransporter (PepT1).
- Intracellular Hydrolysis: Once inside the enterocyte, most absorbed di- and tri-peptides are further hydrolyzed into free amino acids by intracellular peptidases.
- Exit into Bloodstream: The free amino acids are then transported across the basolateral membrane (facing the bloodstream) into the portal circulation, primarily via facilitated diffusion and other transporters, and delivered to the liver.
Summary of Digestion Products for Absorption: The ultimate goal of protein digestion is to convert dietary proteins into free amino acids (the primary form absorbed into the blood), and to a lesser extent, di- and tri-peptides which are then broken down intracellularly.
Amino Acids & Amino Acid Pool/Nitrogen Balance
Differentiate Between Essential and Non-Essential Amino Acids
Amino acids are classified based on the human body's ability to synthesize them de novo (from scratch) or not. This classification is crucial for understanding nutritional requirements and metabolic pathways.
Essential Amino Acids (EAAs):
- Definition: These are amino acids that cannot be synthesized by the human body at all, or cannot be synthesized in sufficient quantities to meet physiological needs. Therefore, they must be obtained from the diet.
- Reason for Essentiality: The human body lacks the necessary enzymatic pathways to synthesize their carbon skeletons from simpler precursors, or it cannot synthesize them fast enough.
- List of Essential Amino Acids (PVT TIM HALL):
- Phenylalanine
- Valine
- Threonine
- Tryptophan
- Isoleucine
- Methionine
- Histidine (often considered essential, especially for infants and during growth, but some texts list it as semi-essential)
- Arginine (semi-essential; the body can synthesize it, but not always enough to meet the demands of rapid growth, especially in infants)
- Leucine
- Lysine
- Dietary Sources: Found in protein-rich foods, particularly "complete proteins" like meat, fish, eggs, dairy, soy, and quinoa, which contain all essential amino acids in adequate proportions.
Non-Essential Amino Acids (NEAAs):
- Definition: These are amino acids that the human body can synthesize de novo from intermediates of central metabolic pathways (like glycolysis, TCA cycle, and pentose phosphate pathway) or from other amino acids. They do not strictly need to be consumed in the diet.
- Reason for Non-Essentiality: The body possesses the necessary enzymatic machinery to synthesize their carbon skeletons and incorporate nitrogen.
- List of Non-Essential Amino Acids: Alanine, Asparagine, Aspartate, Cysteine, Glutamate, Glutamine, Glycine, Proline, Serine, Tyrosine.
- Conditional Essentiality: Some non-essential amino acids can become "conditionally essential" during specific physiological states or diseases. For example:
- Tyrosine becomes essential if dietary phenylalanine is insufficient or if the enzyme converting phenylalanine to tyrosine is deficient (e.g., in PKU).
- Cysteine becomes essential if dietary methionine is insufficient.
- Arginine and Glutamine can become conditionally essential during periods of rapid growth, severe illness, trauma, or stress.
Describe Amino Acid Pool and Nitrogen Balance
These concepts are fundamental to understanding the dynamic state of amino acid metabolism in the body.
The Amino Acid Pool:
- Concept: The "amino acid pool" refers to the total circulating and intracellular free amino acids available in the body at any given time. It's not a physical storage organ, but rather a conceptual reservoir.
- Sources of Amino Acids for the Pool:
- Dietary Protein Breakdown: Digestion and absorption of proteins from food.
- Tissue Protein Degradation (Protein Turnover): Continuous breakdown of existing body proteins.
- De Novo Synthesis: Synthesis of non-essential amino acids.
- Uses of Amino Acids from the Pool:
- Protein Synthesis: Rebuilding and repairing body proteins.
- Synthesis of Non-Protein Nitrogenous Compounds: As discussed earlier (nucleotides, hormones, neurotransmitters, etc.).
- Energy Production/Conversion: Catabolism of amino acids.
- Dynamic Equilibrium: The amino acid pool is in a constant state of flux, with amino acids continuously entering and leaving.
Nitrogen Balance:
- Concept: Nitrogen balance is a measure of the total nitrogen intake versus the total nitrogen excretion. It's used as a proxy for protein metabolism.
- Nitrogen Intake: Primarily from dietary protein. (Protein intake (g) / 6.25 = Nitrogen intake (g)).
- Nitrogen Excretion: Primarily as urea in urine, but also as ammonia, creatinine, uric acid, and small amounts in feces, sweat, and skin cells.
- Nitrogen Equilibrium (Zero Nitrogen Balance):
- Definition: Nitrogen intake equals nitrogen excretion.
- Physiological State: Healthy adults maintaining their body weight and muscle mass.
- Example: A non-growing adult consuming adequate protein.
- Positive Nitrogen Balance:
- Definition: Nitrogen intake is greater than nitrogen excretion. This indicates net protein synthesis and tissue growth.
- Physiological States: Growth (infants, children, adolescents), Pregnancy, Convalescence (recovery from illness), Bodybuilding.
- Example: A growing child who consumes enough protein for new tissue formation.
- Negative Nitrogen Balance:
- Definition: Nitrogen excretion is greater than nitrogen intake. This indicates net protein loss and tissue wasting.
- Physiological States: Inadequate Protein Intake (starvation), Severe Illness/Injury/Trauma (burns, infections), Cancer, Sepsis, Lack of Essential Amino Acids.
- Example: A patient with severe burns, where muscle protein is being broken down to provide amino acids for tissue repair and energy.
States of Nitrogen Balance:
General Reactions of Amino Acid Catabolism
When amino acids are in excess, or when the body needs to convert their carbon skeletons into other molecules, they undergo a series of catabolic reactions. The first and most critical step is the removal of the α-amino group, as this nitrogen cannot be stored and must be detoxified and excreted.
Transamination: Transfer of the Amino Group
- Definition: Transamination is the most common and initial step in the catabolism of most amino acids. It involves the transfer of an α-amino group from an amino acid to an α-keto acid. This reaction is reversible.
- Enzymes: Catalyzed by aminotransferases (also known as transaminases), such as Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST).
- General Reaction:
Amino Acid 1 + α-Keto Acid 2 ⇌ α-Keto Acid 1 + Amino Acid 2 - Example:
Alanine + α-Ketoglutarate ⇌ Pyruvate + Glutamate - Coenzyme: All aminotransferases require pyridoxal phosphate (PLP), derived from Vitamin B6.
- Mechanism of PLP: PLP transiently accepts the amino group from the amino acid and then donates it to the α-keto acid.
- Key Players:
- α-Ketoglutarate: A central amino group acceptor, becoming Glutamate.
- Glutamate: Serves as a collecting point for amino groups.
- Significance: Collects amino groups, allows for interconversion of non-essential amino acids, and serves as a source of diagnostic markers (ALT/AST for liver damage).
Oxidative Deamination: Release of Ammonia
- Definition: Oxidative deamination is the process by which the amino group is removed from an amino acid, typically glutamate, and released as free ammonia (NH₃). This reaction is irreversible.
- Primary Enzyme: The key enzyme is Glutamate Dehydrogenase.
- Location: Found in the mitochondria, particularly high in the liver and kidney.
- Reaction:
Glutamate + NAD(P)⁺ + H₂O → α-Ketoglutarate + NH₄⁺ + NAD(P)H + H⁺ - Coenzymes: Can use either NAD⁺ or NADP⁺.
- Regulation: Glutamate dehydrogenase is allosterically regulated:
- Activated by: ADP, GDP (indicating low energy).
- Inhibited by: ATP, GTP (indicating high energy).
- Significance: This is the major source of ammonia destined for the urea cycle and links amino acid catabolism to the TCA cycle via α-ketoglutarate.
Fate of the Ammonia Produced from Deamination
Ammonia (NH₃) and ammonium ions (NH₄⁺) are highly toxic, especially to the central nervous system. Their detoxification and excretion are crucial.
- Transport to the Liver:
- Glutamine Synthetase: In most peripheral tissues, ammonia is "fixed" to glutamate to form glutamine, a non-toxic transport form.
- Glucose-Alanine Cycle: In muscle, amino groups are transferred to pyruvate to form alanine, which is then transported to the liver.
- Detoxification in the Liver (Urea Cycle): The liver is the primary site for converting toxic ammonia into non-toxic urea.
- Excretion: Urea is transported to the kidneys and excreted in the urine.
Fate of the α-Keto Acid Carbon Skeletons
After removal of the amino group, the remaining carbon skeleton can be channeled into various pathways:
- Glucogenic Amino Acids:
- Definition: Amino acids whose carbon skeletons can be converted into glucose via gluconeogenesis.
- Mechanism: Their α-keto acids are converted into intermediates of the TCA cycle (e.g., α-ketoglutarate, succinyl CoA) or directly into pyruvate.
- Ketogenic Amino Acids:
- Definition: Amino acids whose carbon skeletons can be converted into ketone bodies or fatty acids.
- Mechanism: Their α-keto acids are converted into Acetyl-CoA or Acetoacetyl-CoA.
- List: Only two amino acids are purely ketogenic: Leucine and Lysine.
- Mixed Amino Acids (Glucogenic and Ketogenic):
- Definition: Amino acids whose skeletons yield both glucogenic and ketogenic intermediates.
- List: Phenylalanine, Tyrosine, Tryptophan, Isoleucine, Threonine.
- Energy Production: The α-keto acids can also be directly oxidized in the TCA cycle to generate ATP, especially when amino acids are in excess or energy demands are high.
The Urea Cycle
The Urea Cycle (sometimes called the Ornithine Cycle) is the body's main safety system for handling nitrogen. It is a metabolic pathway (a series of chemical reactions) that occurs primarily in the Liver.
The Main Goal: To turn Ammonia (NH₃), which is highly toxic and dangerous to the brain, into Urea, which is much less toxic and safe to travel through the blood. The kidneys then filter the urea out into urine so it can leave the body.
🔑 Key Vocabulary (Read this first)
- Metabolic Pathway: A step-by-step chain of chemical reactions in the body.
- Mitochondria: The "power plant" inside a cell. This is a separate room inside the cell where the first steps happen.
- Cytosol: The liquid "main floor" of the cell that surrounds the mitochondria. The later steps happen here.
- Enzyme: A special protein that builds or breaks other molecules. Think of it as a worker or a machine.
- ATP: The energy currency of the cell. The body "pays" ATP to make reactions happen.
- Substrate/Reactant: The ingredients used at the start of a reaction.
- Product: The result made at the end of a reaction.
A. Steps and Intermediates of the Urea Cycle
The cycle has 5 distinct steps. It is unique because it happens in two different places within the liver cell. It starts in the Mitochondria and finishes in the Cytosol.
Phase 1: Mitochondrial Reactions (Inside the "Inner Room")
Steps 1 and 2 happen here.
Step 1: Carbamoyl Phosphate Synthesis
⚠️ This is the Rate-Limiting Step (The most critical step)
- Reactants (Ingredients): Ammonia (NH₃) + Bicarbonate (HCO₃⁻).
- Enzyme (The Worker): Carbamoyl Phosphate Synthetase I (CPS-I).
- Product (Result): Carbamoyl Phosphate.
- Energy Cost: Requires 2 ATP. This is an expensive step!
Detailed Note:
This enzyme, CPS-I, lives in the mitochondria. Do not confuse it with CPS-II, which lives in the cytosol and is used to make DNA building blocks (pyrimidines). This distinction is very important.
Step 2: Citrulline Synthesis
- Reactants: Carbamoyl Phosphate + Ornithine.
- Enzyme: Ornithine Transcarbamoylase (OTC).
- Product: Citrulline.
How it works:
Think of Ornithine as a "carrier vehicle." It picks up the Carbamoyl Phosphate to form Citrulline. Once Citrulline is formed, it is able to leave the mitochondria and travel out into the cytosol for the next phase.
Phase 2: Cytosolic Reactions (On the "Main Floor")
Steps 3, 4, and 5 happen here.
Step 3: Argininosuccinate Synthesis
Now that Citrulline has arrived in the cytosol, it meets a new ingredient.
- Reactants: Citrulline + Aspartate.
- Enzyme: Argininosuccinate Synthetase.
- Product: Argininosuccinate.
- Energy Cost: Requires 1 ATP (But it is hydrolyzed to AMP + PPi).
Important Details:
- The Nitrogen Source: The molecule Aspartate is very important because it donates the second nitrogen atom needed to build Urea.
- Energy Math: Even though only 1 ATP molecule is used, it is broken down deeply (into AMP), so the energy cost is equivalent to using 2 ATPs.
Step 4: Arginine Formation
- Reactant: Argininosuccinate.
- Enzyme: Argininosuccinase (also called Argininosuccinate Lyase).
- Products: Arginine + Fumarate.
The Connection:
The product Fumarate is a byproduct (a leftover). However, the body does not waste it. Fumarate enters the TCA Cycle (Krebs Cycle) to help make energy. This links the Urea Cycle to other energy cycles.
Step 5: Urea Cleavage (The Final Cut)
- Reactant: Arginine.
- Enzyme: Arginase.
- Products: Urea + Ornithine.
Completing the Cycle:
- Urea: This is the final safe waste product. It travels to the kidneys to be peed out.
- Ornithine: Notice that we made Ornithine again? This Ornithine is transported back into the mitochondria to start Step 2 again. This is why it is called a "Cycle."
B. Quick Reference: Enzyme Locations
Inside Mitochondria
- Carbamoyl Phosphate Synthetase I (CPS-I)
- Ornithine Transcarbamoylase (OTC)
Inside Cytosol
- Argininosuccinate Synthetase
- Argininosuccinase (Lyase)
- Arginase
C. Regulation: How the Body Controls the Speed
The body is smart. It does not run this cycle at full speed all the time. It regulates (controls) the speed based on how much protein you eat.
1. The "Master Switch": N-Acetylglutamate (NAG)
The enzyme CPS-I (from Step 1) is the rate-limiting enzyme. It acts like a gate. To open the gate, it needs a specific key.
- The Key: A molecule called N-Acetylglutamate (NAG).
- How it works (Allosteric Activation): When NAG attaches to CPS-I, it changes the shape of the enzyme, turning it "ON." Without NAG, CPS-I cannot work.
- Where does the Key (NAG) come from?
- NAG is made by an enzyme called NAG Synthase.
- NAG Synthase is stimulated by Arginine and Glutamate.
- The Logic: If you eat a lot of protein, your Arginine and Glutamate levels go up. This tells the body to make more NAG. More NAG turns on the Urea Cycle to clean up the waste from the protein.
2. Substrate Availability (Supply and Demand)
Simply put, if there is more "stuff" to process, the cycle goes faster. The rate increases if there are higher levels of Ammonia, Bicarbonate, or Aspartate available.
3. Long-Term Induction (Adaptation)
If you change your lifestyle for a long time, the body physically builds more of the urea cycle enzymes.
- High-Protein Diet: Eating lots of meat creates more nitrogen waste, so the liver builds more enzymes to cope.
- Starvation: During starvation, the body breaks down its own muscles (protein) for energy. This releases nitrogen, so the body must increase enzyme levels to handle the load.
D. Why is the Urea Cycle So Important?
- Detoxification (Safety): This is the #1 reason. Ammonia is toxic to neurons (brain cells). The cycle converts it into Urea, which is safe. Without this cycle, ammonia builds up (Hyperammonemia), leading to coma or death.
- Nitrogen Excretion: We cannot store excess nitrogen. Urea is the main vehicle for carrying nitrogen out of the body in urine.
- Balance (Homeostasis): It keeps the nitrogen levels in the body stable.
- Metabolic Connection: By producing Fumarate (in Step 4) and using Aspartate, it connects to the TCA cycle (energy production) and Gluconeogenesis (making sugar).
Summary: The "Math" of the Cycle
If we look at the Urea Cycle as one big equation, here is what goes in and what comes out.
Inputs (Cost)
- 2 Ammonia (NH₃): One is free ammonia, the second comes from Aspartate.
- 1 CO₂: Comes from Bicarbonate (HCO₃⁻).
- 3 ATP: This is the energy cost (used in Step 1 and Step 3).
Outputs (Result)
- 1 Urea: The waste product.
- 1 Fumarate: Sent to the TCA cycle.
- 2 ADP + 1 AMP: The leftovers of the used energy.
Overall Chemical Reaction:
NH₄⁺ + HCO₃⁻ + Aspartate + 3 ATP → Urea + Fumarate + 2 ADP + AMP + 4 Pi + H₂O
Classification & Metabolism of Amino Acids
Once the body removes the nitrogen (amino group) from an amino acid, what is left? We call the remaining part the "Carbon Skeleton."
The Big Question: What does the body do with this Carbon Skeleton?
The answer depends on the specific amino acid. It can be turned into Glucose (Sugar), Ketones/Fat, or Both.
1. Classifying Amino Acids by Their Products
We classify amino acids into three groups based on what they become after they are broken down (catabolized).
A. Glucogenic Amino Acids
"Gluco" = Glucose (Sugar) | "Genic" = Creating
Definition: These are amino acids whose carbon skeletons can be converted into Pyruvate or intermediates of the TCA Cycle (like α-ketoglutarate, succinyl CoA, fumarate, or oxaloacetate).
Why does this matter? (Significance):
- All these intermediates can be used to make new Glucose through a process called Gluconeogenesis.
- Scenario: Imagine you are starving or fasting. Your brain needs glucose to survive. The body breaks down these amino acids to make that vital sugar.
Examples (Sorted by what they enter):
- Enter as Pyruvate: Alanine, Cysteine, Glycine, Serine, Threonine, Tryptophan.
- Enter as α-Ketoglutarate: Arginine, Glutamate, Glutamine, Histidine, Proline.
- Enter as Succinyl CoA: Isoleucine, Methionine, Threonine, Valine.
- Enter as Fumarate: Aspartate, Phenylalanine, Tyrosine.
- Enter as Oxaloacetate: Asparagine, Aspartate.
B. Ketogenic Amino Acids
"Keto" = Ketones/Fat
Definition: These amino acids convert into Acetyl-CoA or Acetoacetyl-CoA.
Important Rule: These CANNOT make Glucose.
Why? Because in mammals, the step turning Pyruvate into Acetyl-CoA is irreversible (one-way only). Once you are Acetyl-CoA, you cannot go back up to become sugar.
Significance:
- They are used to make Ketone Bodies (alternative fuel for the brain during long starvation) or Fatty Acids (fat storage).
The "Exclusive" List (Only 2):
There are only two amino acids that are purely ketogenic:
- Leucine
- Lysine
(Mnemonic: The "L" amino acids differ from the rest).
C. Mixed Amino Acids
Glucogenic AND Ketogenic
Definition: These are flexible. When they break down, part of their skeleton becomes a precursor for glucose, and another part becomes a precursor for ketones/fat.
Examples:
- Phenylalanine
- Tyrosine
- Tryptophan
- Isoleucine
- Threonine
Note: You will see these names appear in the Glucogenic list as well because they fit both categories.
Visual Summary: Where do they go?
2. Metabolism of Specific Amino Acid Groups
While all amino acids undergo transamination (removing nitrogen), the path for their carbon skeletons is unique. We will look at three special groups.
A. Branched-Chain Amino Acids (BCAAs)
Who are they? Leucine, Isoleucine, Valine.
Unique Feature: Unlike most amino acids that go to the Liver, BCAAs are primarily metabolized in the Muscles (and other peripheral tissues).
Why? The liver lacks the first enzyme needed to break them down.
The Pathway:
Step 1: Transamination (Moving the Nitrogen)
The enzyme Branched-chain Aminotransferase (BCAT) removes the amino group.
- Location: Skeletal muscle, kidney, brain.
- Result: We are left with α-Keto Acids (specifically called BCKAs).
Step 2: Oxidative Decarboxylation (The Irreversible Step)
The BCKAs are processed by a massive enzyme complex called Branched-Chain α-Keto Acid Dehydrogenase (BCKD).
- Required Helpers (Coenzymes): It needs 5 friends to work: TPP, FAD, NAD+, Lipoic Acid, and Coenzyme A.
If a person is born without this BCKD enzyme complex, they cannot break down BCAAs. The "Keto Acids" build up in the blood and urine. The urine smells sweet like maple syrup/burnt sugar. This accumulation is toxic to the brain (neurotoxic) and can cause death if not treated.
Step 3: The End Products
- Leucine → Becomes Acetyl-CoA (Purely Ketogenic).
- Valine → Becomes Succinyl-CoA (Purely Glucogenic).
- Isoleucine → Becomes Acetyl-CoA AND Succinyl-CoA (Mixed).
Significance of BCAAs:
- Muscle Fuel: A key energy source during exercise.
- Building Muscle: Leucine signals the muscle to start building protein.
- Nitrogen Transport: They help form Alanine, which carries nitrogen safely to the liver.
B. Aromatic Amino Acids
These amino acids have a ring structure (benzene ring). They are Phenylalanine, Tyrosine, and Tryptophan.
1. Phenylalanine & Tyrosine
Phenylalanine is an Essential amino acid (you must eat it). Tyrosine is made from Phenylalanine.
Phenylalanine + O₂ + BH4 → Tyrosine + H₂O + BH2
- Enzyme: Phenylalanine Hydroxylase (PAH).
- Coenzyme: Tetrahydrobiopterin (BH4).
If the enzyme PAH is missing or broken:
- Phenylalanine cannot turn into Tyrosine.
- Phenylalanine builds up to dangerous levels.
- This is toxic to the brain and causes severe intellectual disability.
- Treatment: A lifelong diet with very low Phenylalanine.
What does Tyrosine become?
- Catabolism: Broken down into Fumarate (Glucogenic) and Acetoacetate (Ketogenic).
- Special Products: Tyrosine is the raw material for:
- Catecholamines: Dopamine, Norepinephrine, Epinephrine (Adrenaline).
- Thyroid Hormones: T3 and T4.
- Melanin: The pigment for skin and hair.
2. Tryptophan (Essential)
Tryptophan has a very complex breakdown path. It is a Mixed amino acid.
- End Products: Alanine (Glucogenic) and Acetyl-CoA (Ketogenic).
- Important Derivatives (What it makes):
- Serotonin: Regulates mood and appetite.
- Melatonin: Regulates sleep cycles.
- Niacin (Vitamin B3): We can make a small amount of this vitamin from Tryptophan.
C. Sulfur-Containing Amino Acids
These contain Sulfur atoms: Methionine and Cysteine.
1. Methionine (Essential)
Methionine is famous for being a "Donor." It gives away methyl groups (CH3) to help build other things.
The Cycle of Methionine (Step-by-Step):
- Activation: Methionine + ATP → SAM (S-Adenosylmethionine).
Think of SAM as "Super Active Methionine." - Donation: SAM gives away its Methyl group and becomes SAH.
- Hydrolysis: SAH is broken down into Homocysteine.
The Fate of Homocysteine (The Fork in the Road):
Homocysteine is dangerous if it stays. It must go somewhere. It has two choices:
Turn back into Methionine.
Needs: Vitamin B12 + Folate.
Turn into Cysteine.
Needs: Vitamin B6.
If the enzymes needed to clear Homocysteine don't work (genetic defect), Homocysteine levels rise. This causes heart problems, skeletal deformities, and eye issues.
2. Cysteine
Cysteine is usually made from Methionine. However, if you don't eat enough Methionine, Cysteine becomes essential.
- Catabolism: It breaks down into Pyruvate (Glucogenic) and Sulfate.
- Important Derivatives:
- Glutathione: The body's master antioxidant (detoxifier).
- Taurine: Found in bile.
- Coenzyme A: Vital for energy metabolism.
Interconnectedness of Metabolism
Amino acid metabolism does not happen in a lonely island. It is like a city with many roads connecting to other neighborhoods. It is tightly linked to Carbohydrates (Sugar) and Lipids (Fats).
Why is this important?
This connection gives the body "Metabolic Flexibility." It ensures you can survive different situations—whether you just ate a huge meal (feast) or haven't eaten for days (famine/starvation).
A. Connection to Carbohydrate (Sugar) Metabolism
1. Glycolysis and Gluconeogenesis
Many amino acids break down into Pyruvate. Pyruvate is a famous "crossroads" molecule. Once an amino acid becomes Pyruvate, it has three choices:
- Choice 1 (Energy): Turn into Acetyl-CoA and burn in the TCA cycle.
- Choice 2 (No Oxygen): Turn into Lactate (Lactic Acid).
- Choice 3 (Make Sugar): Turn into Oxaloacetate, which is then used to build Glucose (Gluconeogenesis).
2. The Glucose-Alanine Cycle (Muscle-Liver Link)
This is a specific transport system that connects your muscles to your liver. Think of Alanine as a "Taxi."
- In the Muscle: When muscles work, they make waste (Pyruvate) and breakdown amino acids (Nitrogen). They combine these to make Alanine.
- The Journey: Alanine travels through the blood to the Liver.
- In the Liver: The Liver separates them.
- The Nitrogen goes to the Urea Cycle (to be excreted).
- The Pyruvate is turned back into Glucose.
- Return Trip: The Glucose is sent back to the muscle to be used as fuel again.
B. Connection to Lipid (Fat) Metabolism
When amino acids break down into Acetyl-CoA, they enter the world of fats.
1. Making Fat (Storage)
If you have too much energy (you ate too much protein and carbs), the body uses the Acetyl-CoA from amino acids to synthesize Fatty Acids for storage.
2. Making Ketones (Survival)
If you are starving, the body turns Acetyl-CoA into Ketone Bodies. These serve as emergency fuel for the Brain and Heart.
Note: Acetyl-CoA is also used to make Cholesterol.
C. Connection to the TCA Cycle (Krebs Cycle)
The TCA cycle is the "Central Hub" or the "Roundabout" of metabolism.
Concept: Anaplerosis ("Topping Up")
Sometimes, the TCA cycle runs out of ingredients (intermediates) because they were taken away to build other things. Glucogenic amino acids can be broken down to refill these ingredients. This refilling process is called Anaplerosis.
Energy Production: Ultimately, the carbon skeletons of all amino acids can be fully burned in this cycle to produce ATP (Energy).
D. Nucleotide Metabolism
DNA and RNA need Nitrogen and Carbon to be built.
- Nitrogen Source: Supplied by Glutamine, Aspartate, and Glycine.
- Carbon Source: Supplied by Glycine.
E. Regulatory Cross-Talk
Hormones control these choices:
- Insulin (Fed State): Says "Build!" Promotes protein synthesis.
- Glucagon (Fasting State): Says "Break down!" Stimulates turning amino acids into glucose.
- ATP Levels: High ATP means "We are full," favoring synthesis. Low ATP means "We are hungry," favoring breakdown for energy.
Common Metabolic Disorders
These are "Inborn Errors of Metabolism." They are usually genetic (inherited from parents). A specific enzyme is broken or missing. This causes a traffic jam: Toxic precursors build up and Essential products run out.
1. Phenylketonuria (PKU)
Defect: Phenylalanine Hydroxylase (PAH)
The Mechanism:
The body cannot convert Phenylalanine into Tyrosine.
- Accumulation: Phenylalanine builds up. It turns into toxic acids (Phenylpyruvate) causing a "Mousy" (mouse-like) odor in urine.
- Deficiency: Tyrosine becomes essential (because we can't make it). Less melanin is made, leading to fair skin/hair.
🚨 Clinical Signs & Danger:
- Neurotoxicity: High Phenylalanine destroys the brain.
- Symptoms: Severe intellectual disability, microcephaly (small head), seizures.
Treatment: Lifelong diet restriction. No meat, dairy, or aspartame. Special formula required.
2. Maple Syrup Urine Disease (MSUD)
Defect: Branched-Chain α-Keto Acid Dehydrogenase (BCKD)
- The Problem: Cannot break down Leucine, Isoleucine, and Valine (BCAAs).
- Symptoms (Neonatal): Poor feeding, vomiting, coma, seizures.
- Outcome: Severe brain damage or death if not treated immediately.
- Treatment: Diet strictly limiting BCAAs.
3. Alkaptonuria (Black Urine Disease)
Defect: Homogentisate 1,2-Dioxygenase (HGD)
This is a defect in Tyrosine breakdown. A chemical called Homogentisic Acid (HGA) builds up.
4. Homocystinuria
Defect: Cystathionine β-Synthase (CBS)
The Problem: Methionine and Homocysteine levels are too high. Cysteine becomes essential.
Clinical Appearance (Marfan-like):
- Eyes: Dislocation of the lens (Ectopia Lentis).
- Skeleton: Tall, thin body with long limbs (Marfanoid habitus). Osteoporosis.
- Vascular (Critical): High risk of blood clots (Thrombosis), causing strokes or heart attacks at a young age.
Treatment: High doses of Vitamin B6 (if responsive), low methionine diet, and Betaine.
5. Urea Cycle Disorders (UCDs)
Defect: Any enzyme in the Urea Cycle
The Killer: Hyperammonemia (High Ammonia).
What happens? Ammonia is not removed. It reaches the brain and causes:
- Vomiting and Lethargy (tiredness).
- Cerebral Edema (Brain swelling).
- Coma and Death.
Treatment: Restrict protein intake. Use drugs to scavenge ammonia. Liver transplant may be needed.
Nitrogen Catabolism & Toxicity
While we know how the Urea Cycle works, we must understand why and when the body decides to break down proteins, and exactly why ammonia is so dangerous to the brain.
1. When does Protein Catabolism happen?
The body does not store protein like it stores fat. It breaks it down in three specific situations:
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Normal Turnover: Old proteins are broken down to build new ones. Any extras are destroyed.
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Dietary Surplus: If you eat more protein than you need, the body cannot store it. It breaks the surplus down for energy.
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Starvation or Diabetes: When sugar (carbohydrates) is unavailable, the body breaks down its own muscle protein to use as emergency fuel.
2. Mechanisms of Nitrogen Removal
Before we can burn the amino acid for energy, we must remove the nitrogen. This happens in two ways.
A. Transamination (The Swap)
We swap the Amino Group onto α-Ketoglutarate to form Glutamate.
- Enzymes: Aminotransferases (like AST and ALT).
- Coenzyme Required: PLP (Vitamin B6).
- Clinical Note: High levels of AST or ALT in the blood indicate Liver or Heart damage (the cells burst and leak the enzyme).
B. Deamination (The Removal)
Removing the amino group completely to release Ammonia (NH₄⁺).
Performed by Glutamate Dehydrogenase. It uses NAD+ or NADP+. This is the main way Glutamate releases ammonia in the liver.
Specific to Serine and Threonine (because they have an -OH group). Used enzymes called Dehydratases (e.g., Serine Dehydratase).
3. Transport: The Ammonia Taxi System
Ammonia is toxic. It cannot swim freely in the blood. It must be carried by safe "Taxi" molecules.
Taxi 1: Glutamine
From Brain & Kidney → To Liver
Ammonia + Glutamate → Glutamine.
Glutamine is neutral and non-toxic. It travels to the liver, where the enzyme Glutaminase breaks it back down to release the ammonia.
Taxi 2: Alanine
From Muscle → To Liver
Muscle waste (Pyruvate) + Nitrogen → Alanine.
Alanine travels to the liver. The liver takes the Nitrogen for Urea, and turns the Pyruvate back into Glucose (Glucose-Alanine Cycle).
4. Clinical Pathology: When things go wrong
Blood Urea Nitrogen (BUN)
- Normal Range: 20 – 40 mg/dL.
- Significance: High BUN usually means the Kidneys are not working (they aren't filtering the urea out).
- Causes of High BUN (Uremia):
- Pre-renal: Blood flow issue (heart failure).
- Renal: Kidney damage.
- Post-renal: Blockage (kidney stones/tumor).
Why is Ammonia Toxic to the Brain?
If the liver fails (Cirrhosis) or the Urea Cycle has a genetic defect, ammonia builds up. It causes tremors, slurred speech, coma, and death. But why?
To try and clean up the ammonia, the brain combines it with α-Ketoglutarate to make Glutamate.
The Problem: α-Ketoglutarate is needed for the Krebs Cycle (energy). If you use it all up to fight ammonia, the Krebs cycle stops. The brain runs out of ATP (Energy).
Excess Glutamate creates excess GABA, an inhibitory neurotransmitter. This slows down brain signals (causing lethargy/coma).
Accumulation of Glutamine inside brain cells pulls water in (osmosis). This causes Cerebral Edema (Brain Swelling), which can be fatal.
Treatment Note: Lactulose
Hepatic Encephalopathy (Brain damage from liver ammonia) is often treated with Lactulose, which helps pull ammonia into the gut to be pooped out.
Biosynthesis of Amino Acids
Biosynthesis (Anabolism) is the process of the body building complex molecules from simple ones. In this section, we explore how the body creates Amino Acids, which are the building blocks of proteins, nucleotides, and lipids.
Introduction & Key Concepts
- Ancient Pathways: These chemical pathways are very old in evolutionary history.
- Shared Roads: Building (Anabolism) often uses the same ingredients as Breaking Down (Catabolism).
- Source of Carbon: The "backbones" of amino acids come from three main places:
- Glycolysis
- Citric Acid Cycle (TCA)
- Pentose Phosphate Pathway
- Stereochemistry: Our body specifically makes L-Amino Acids. This shape is enforced during the Transamination step.
1. Nitrogen Fixation: Getting Nitrogen
Before we can build an amino acid, we need Nitrogen. The air is 80% Nitrogen Gas (N₂), but our bodies cannot use gas. It must be "fixed" (turned into a solid/liquid form like Ammonia, NH₃).
Who fixes Nitrogen?
- 60% - Microorganisms: Specific bacteria (Diazotrophs) do the heavy lifting. They use ATP and a protein called Ferredoxin.
- 15% - Nature's Power: Lightning and UV radiation have enough energy to break nitrogen bonds.
- 25% - Industrial: Humans do it chemically.
The Industrial Method (Haber Process)
Fritz Haber discovered how to do this in a factory.
Equation: N₂ + 3H₂ → 2NH₃
The Biological Machine: Nitrogenase Complex
Bacteria use a complex enzyme system to turn N₂ into NH₃. This system has two distinct parts working together.
Part 1: The Reductase (The "Fe Protein")
Function: This is the power supply. It gathers electrons.
- Contains a 4Fe-4S center (Iron-Sulfur cluster).
- It hydrolyzes (burns) ATP.
- This burning causes a shape change (conformational change) that pushes electrons to Part 2.
Part 2: The Nitrogenase (The "MoFe Protein")
Function: This is the factory where the chemistry happens.
- Structure: It is an α2β2 tetramer (4 subunits) weighing 240 kD.
- The P-Cluster: Where electrons enter.
- The Cofactor: It contains an Iron-Molybdenum (FeMo) cofactor. This specific metal cluster is what binds to Nitrogen (N₂) and reduces it to Ammonia (NH₃).
2. Assimilation: Bringing Ammonia into the Body
Once we have Ammonia (NH₄⁺), we must attach it to a carbon molecule to start making amino acids. This happens through two main "Gatekeeper" enzymes: Glutamate and Glutamine.
Gate 1: Glutamate Dehydrogenase
This enzyme combines Ammonia with α-Ketoglutarate (from the TCA cycle).
Significance: Most other amino acids get their α-amino group (their nitrogen) from Glutamate via Transamination.
Gate 2: Glutamine Synthetase
This enzyme adds a second nitrogen to Glutamate to make Glutamine.
Significance: The sidechain nitrogen of Glutamine is used to build complex amino acids like Tryptophan and Histidine.
3. The Amino Acid Families
Amino acids are grouped into "Families" based on which carbon skeleton they come from.
| Origin (Parent) | Amino Acids Produced (Children) |
|---|---|
| Oxaloacetate | Aspartate → Asparagine, Methionine, Threonine, Lysine |
| Pyruvate | Alanine, Valine, Leucine, Isoleucine |
| α-Ketoglutarate | Glutamate → Glutamine, Proline, Arginine |
| 3-Phosphoglycerate | Serine → Glycine, Cysteine |
| PEP + Erythrose-4P | Phenylalanine, Tyrosine, Tryptophan (Aromatic) |
| Ribose-5-Phosphate | Histidine |
Essential vs. Non-Essential
Non-Essential (We make them)
These pathways are simple (few steps).
Examples: Alanine, Glutamate, Aspartate.
Essential (Must eat them)
These pathways are complex (many steps). We lost the ability to make them.
Examples: Histidine, Lysine, Methionine, Valine.
Observation: The graph in the slides shows a direct link—Essential amino acids require many more enzymatic steps to create than non-essential ones.
4. Details of Specific Pathways
A. Aspartate and Alanine (Transamination)
These are made by simply swapping the oxygen group for an amino group using Glutamate.
- Oxaloacetate + Glutamate ↔ Aspartate + α-Ketoglutarate
- Pyruvate + Glutamate ↔ Alanine + α-Ketoglutarate
B. Asparagine (Amidation)
We take Aspartate and add another nitrogen.
Aspartate + ATP + Glutamine (Donor) → Asparagine + Glutamate + AMP + PPi
C. Proline and Arginine
Both are made from Glutamate.
- Glutamate is reduced to Glutamic γ-semialdehyde.
- This intermediate cyclizes (forms a ring) to eventually become Proline.
- Or, through the urea cycle (involving Ornithine), it becomes Arginine.
D. Serine and Glycine
- Start: 3-Phosphoglycerate (from glycolysis).
- Oxidation: Converted to 3-Phosphohydroxypyruvate.
- Transamination: Converted to 3-Phosphoserine.
- Hydrolysis: Converted to Serine.
How to make Glycine?
The enzyme Serine Transhydroxymethylase removes a carbon from Serine to make Glycine. This requires Tetrahydrofolate.
5. One-Carbon Metabolism (The Carriers)
The body often needs to move single carbon atoms (methyl groups) around to build things. It uses two main "Postmen" for this.
Carrier 1: Tetrahydrofolate (THF)
Derived from Folic Acid (Vitamin B9).
- It carries 1-carbon groups on its Nitrogen atoms (N5 or N10).
- It can carry them in different "Oxidation States" (Methyl, Methylene, Formyl, etc.).
- Limit: It is not strong enough to donate methyl groups for some hard reactions (like DNA methylation).
Carrier 2: S-Adenosylmethionine (SAM)
The "Super" Donor.
- Made from Methionine + ATP.
- It has a high "Methyl Transfer Potential" (it really wants to give away its methyl group).
- Use: Used for DNA methylation and other difficult synthesis tasks.
The Activated Methyl Cycle:
Methionine → SAM → (Donates CH3) → S-Adenosylhomocysteine → Homocysteine → (Regenerates) → Methionine
6. Aromatic Amino Acids
These are the amino acids with rings: Phenylalanine, Tyrosine, and Tryptophan.
The Shikimate & Chorismate Pathway
Plants and bacteria use this pathway (humans don't—that's why these are essential for us).
- Key Intermediate: Chorismate.
- Chorismate branches out to form Phenylalanine and Tyrosine (via Prephenate).
- Chorismate also converts to Anthranilate to eventually form Tryptophan (using PRPP).
The weedkiller Glyphosate works by inhibiting the enzyme that makes Chorismate. Because humans do not have this enzyme, Roundup is toxic to plants but relatively safe for humans.
7. Regulation: Controlling the Factory
The body doesn't waste energy. If we have enough amino acids, we stop making them. This is done via Feedback Inhibition.
Basic Feedback Inhibition
The final product (Z) goes back and inhibits the first enzyme (A → B).
A → B → C → D → E → Z (Z blocks A)
Example: Serine
Serine inhibits the enzyme 3-phosphoglycerate dehydrogenase.
Complex Regulation Strategies
- Enzyme Multiplicity: Having 3 versions of the same enzyme (isozymes). One is inhibited by Lysine, one by Methionine, one by Threonine. This allows fine-tuning (seen in Aspartokinase).
- Cumulative Feedback: The enzyme is only partially stopped by one product. To stop it completely, ALL products must be present (Example: Glutamine Synthetase).
- Cascade Control (Glutamine Synthetase): This enzyme is so important it has a "Master Switch." It is controlled by Adenylylation (adding AMP).
- Adenylylated = Less Active.
- Deadenylylated = More Active.
- This switch is controlled by regulatory proteins (Pa/Pd) sensing ATP and α-Ketoglutarate levels.
8. Amino Acid Derivatives
Amino acids are not just for proteins. They are precursors for many vital biomolecules.
Made from Glutamate + Cysteine + Glycine. It is the body's main antioxidant and sulfhydryl buffer.
Made from Arginine. It is a short-lived signal molecule (vasodilator).
Made from Glycine + Succinyl-CoA. Essential for blood (Hemoglobin).
Tyrosine → Dopamine/Adrenaline.
Tryptophan → Serotonin.
Histidine → Histamine.
Amino Acid Carbon Skeleton Catabolism
Introduction: When we break down amino acids, we first remove the Nitrogen (Amino group). What is left is called the "Carbon Skeleton" (the Alpha-Keto Acid).
The Main Goal:
To turn these skeletons into energy. They must be converted into one of the 7 molecules that can enter the central energy pathways (TCA Cycle or Glycolysis).
1. Classification: What do they become?
We categorize amino acids based on their final product.
A. Glucogenic
Makes Glucose (Sugar)
These turn into Pyruvate or TCA cycle intermediates (like Oxaloacetate).
- Alanine, Arginine
- Asparagine, Aspartate
- Cysteine, Glutamate
- Glutamine, Glycine
- Proline, Serine, Histidine
- Methionine, Valine
B. Ketogenic
Makes Ketones/Fat
These turn into Acetyl-CoA. They cannot become sugar.
- Leucine
- Lysine
C. Mixed
Makes Both
Part of the molecule becomes sugar, part becomes fat.
- Tyrosine
- Isoleucine
- Phenylalanine
- Tryptophan
- Threonine
2. Metabolism of Glycine & Threonine
Glycine Degradation
Glycine has 3 pathways to be broken down:
- Pathway 1 (Conversion to Serine):
Enzyme: Serine Hydroxymethyltransferase.
Requires: Tetrahydrofolate (Folate) and Pyridoxal Phosphate (Vitamin B6). - Pathway 2 (Major Animal Pathway):
Oxidative cleavage breaks Glycine into CO₂, Ammonia (NH₄⁺), and a methylene group (-CH₂-). - Pathway 3: Does not lead to Pyruvate (less common).
Threonine Degradation
Threonine has two roads it can take:
Threonine is turned into Glycine first, then into Pyruvate. This accounts for only 10-30% of breakdown in humans.
This is the primary way humans handle Threonine. It yields Propionyl-CoA, which eventually becomes Succinyl-CoA.
3. Amino Acids Forming Acetyl-CoA
Seven amino acids break down into Acetyl-CoA. We will focus on the most clinically important pathway: Phenylalanine and Tyrosine.
The Phenylalanine → Tyrosine Pathway
Step 1: Hydroxylation
Phenylalanine is converted to Tyrosine by the enzyme Phenylalanine Hydroxylase.
Tetrahydrobiopterin (BH4)
BH4 donates electrons to the reaction and becomes BH2. It must be recharged back to BH4 to work again.
Phenylketonuria (PKU) occurs if Phenylalanine Hydroxylase is missing. Phenylalanine builds up and damages the brain.
Step 2: Tyrosine Breakdown
Tyrosine is further broken down to produce Fumarate and Acetoacetate.
If the enzyme Homogentisate oxidase is missing, Homogentisate accumulates. This causes Alkaptonuria (Black Urine Disease).
4. Amino Acids Forming α-Ketoglutarate
Five amino acids enter the cycle here: Proline, Glutamate, Glutamine, Arginine, Histidine.
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1. Glutamine:
Uses the enzyme Glutaminase to donate its amide nitrogen, becoming Glutamate.
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2. Proline:
Proline is a ring. The ring is opened (oxidized) to form a Schiff base, then hydrolyzed to form Glutamate γ-semialdehyde, which becomes Glutamate.
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3. Arginine:
Converted to Ornithine (in the Urea Cycle). Ornithine is then converted to Glutamate γ-semialdehyde.
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4. Histidine:
Follows a complex multistep path. Key detail: One carbon is removed using Tetrahydrofolate as a cofactor.
5. Amino Acids Forming Succinyl-CoA
These are Methionine, Isoleucine, Threonine, and Valine.
The Propionyl-CoA Pathway
All four of these amino acids eventually turn into Propionyl-CoA (a 3-carbon unit). The body must turn this into Succinyl-CoA (a 4-carbon unit) to use it.
The Critical Conversion Steps:
- Carboxylation: Propionyl-CoA adds a carbon to become Methylmalonyl-CoA. (Needs Biotin).
- Epimerization: The molecule is rearranged.
- Isomerization (The Mutase Step): Methylmalonyl-CoA is turned into Succinyl-CoA.
Important: This enzyme (Methylmalonyl-CoA Mutase) requires Vitamin B12 (Cobalamin).
If the B12-dependent mutase enzyme is missing, Methylmalonyl-CoA builds up. This causes severe metabolic acidosis.
6. Branched-Chain Amino Acids (BCAAs)
The BCAAs are Leucine, Isoleucine, and Valine.
Where does this happen?
Muscle, Adipose, Kidney, Brain.
NOT in the Liver. The Liver is missing the first enzyme (Aminotransferase) needed for BCAAs.
The BCKD Complex
After the amino group is removed, we are left with Alpha-Keto Acids. These are processed by a massive enzyme called the Branched-Chain α-Keto Acid Dehydrogenase (BCKD) Complex.
This complex performs "Oxidative Decarboxylation" (removing carbon as CO₂).
- Defect: The BCKD complex is broken.
- Result: Alpha-Keto acids accumulate in the blood and urine.
- Symptom: Urine smells sweet like Maple Syrup or burnt sugar.
- Danger: Causes mental retardation and death in infancy if untreated.
- Treatment: Strict diet restricting Valine, Isoleucine, and Leucine.
7. Asparagine and Aspartate
Destination: Oxaloacetate
These ultimately enter the cycle as Oxaloacetate.
- Asparagine is hydrolyzed by the enzyme Asparaginase. It releases NH₄⁺ and becomes Aspartate.
- Aspartate undergoes transamination (swaps Nitrogen) to become Oxaloacetate.
Biochemistry: Amino Acid Metabolism
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