Nov 24, 2025 PDF Available

Topic Overview

⭐ General Amino Acid Metabolism

(Urea Cycle, One-Carbon Metabolism)
Digestion of Proteins & Absorption of Amino Acids

These notes cover the first section of the chapter:
✔ Digestion of dietary proteins
✔ Absorption of amino acids & peptides
✔ High-yield mechanisms and clinical points

Everything is pointwise and perfect for MBBS exam preparation.

⭐ Digestion of Proteins

Protein digestion begins in the stomach and is completed in the small intestine.

⭐ 1. Digestion in the Stomach

a. Hydrochloric Acid (HCl)

Secreted by parietal cells
Denatures proteins → opens peptide bonds
Provides pH 1–2 (optimal for pepsin)

b. Pepsin

Chief cells secrete pepsinogen (inactive)
HCl converts pepsinogen → pepsin
Pepsin is an endopeptidase
Cleaves peptide bonds involving aromatic amino acids (Phe, Tyr, Trp)

c. Product of gastric digestion

Large polypeptides
Some free amino acids
Stimulates CCK release in duodenum

⭐ 2. Digestion in the Small Intestine

Protein digestion is mostly completed here.

a. Hormonal Regulation

CCK (Cholecystokinin):
- Stimulates pancreatic enzyme secretion
- Slows gastric emptying
Secretin:
- Stimulates bicarbonate secretion → neutralizes acid

⭐ b. Pancreatic Proteases (Released as zymogens)

Zymogen	Activated Form	Activator	Function
Trypsinogen	Trypsin	Enteropeptidase	Activates other proteases; cleaves Lys, Arg
Chymotrypsinogen	Chymotrypsin	Trypsin	Cleaves aromatic AAs
Proelastase	Elastase	Trypsin	Cleaves small neutral AAs
Procarboxypeptidase A/B	Carboxypeptidase A/B	Trypsin	Exopeptidase: removes C-terminal AA

Trypsin is the master activator of all pancreatic zymogens.

⭐ c. Intestinal Enzymes

Aminopeptidases – remove N-terminal amino acids
Dipeptidases & Tripeptidases – break small peptides to amino acids
Enteropeptidase – activates trypsinogen

⭐ Products of Digestion

Free amino acids
Dipeptides
Tripeptides

All are absorbable forms.

⭐ Absorption of Amino Acids

Occurs mainly in jejunum.

⭐ 1. Absorption of Free Amino Acids

a. Na⁺-Dependent Transporters

Most amino acids absorbed by secondary active transport
Requires:
- Na⁺ gradient (maintained by Na⁺/K⁺ ATPase)
- Specific carriers for:
  - Neutral AAs
  - Basic AAs
  - Acidic AAs
  - Imino acids (proline)

b. Na⁺-Independent Transporters

For some neutral and basic AAs
Facilitated diffusion at basolateral membrane releases AAs into blood

⭐ 2. Absorption of Dipeptides & Tripeptides

PEPT1 Transporter

H⁺-dependent cotransporter
High capacity
Most dietary protein is absorbed as di- and tripeptides, then hydrolyzed intracellularly

⭐ 3. Clinical Correlations

a. Cystinuria

Defect in transporter for cystine, lysine, arginine, ornithine
Causes kidney stones (hexagonal cystine crystals)

b. Hartnup Disease

Defect in absorption of neutral amino acids
Causes pellagra-like features due to tryptophan deficiency

c. Pancreatic insufficiency

Low trypsin/chymotrypsin
Causes protein malabsorption → steatorrhea

⭐ High-Yield Summary

HCl denatures proteins; pepsin begins hydrolysis.
Enteropeptidase activates trypsin → activates all pancreatic proteases.
Aminopeptidases, dipeptidases complete digestion on brush border.
Amino acids absorbed by Na⁺-dependent active transport.
Dipeptides/tripeptides absorbed by PEPT1 (H⁺ dependent).
Cystinuria involves dibasic AA transporter defect.

⭐ Meister Cycle (γ-Glutamyl Cycle)

The Meister cycle is a pathway for transport of amino acids into cells, especially in kidney, intestine, and liver.
It also regenerates glutathione (GSH), a major antioxidant.

⭐ Key Components

Glutathione (GSH)
Enzymes in membrane & cytosol
Transports neutral amino acids

⭐ Steps of Meister Cycle

1. γ-Glutamyl Transpeptidase (GGT) Reaction

Located on cell membrane
Transfers γ-glutamyl group from GSH to an amino acid entering the cell

GSH + Amino acid → γ-Glutamyl amino acid (outside cell)

Cysteinyl-glycine is released.

2. Transport Into Cell

The γ-glutamyl amino acid is transported into cytosol.

3. Hydrolysis Inside Cell

γ-Glutamyl cyclotransferase removes the amino acid → forms 5-oxoproline.

4. ATP-Dependent Recycling

5-oxoproline → glutamate → forms glutathione again.

This requires 2 ATP molecules.

⭐ Functions of the Meister Cycle

Facilitates amino acid absorption into cells
Regenerates glutathione (antioxidant)
Maintains redox balance
Important in detoxification (liver)

⭐ Clinical Note

GGT is a key clinical enzyme:
- Elevated in alcoholic liver disease
- Elevated with enzyme-inducing drugs (phenytoin, rifampicin)

⭐ Intracellular Protein Degradation

Cells constantly degrade proteins to remove damaged, misfolded, or short-lived proteins.
Two major pathways exist:

Lysosomal degradation
Ubiquitin-proteasome pathway

⭐ 1. Lysosomal Protein Degradation

Occurs inside lysosomes, using acidic hydrolases.

Key Features

Degrades extracellular proteins, membrane proteins, and long-lived proteins
ATP-independent
Uses cathepsins (lysosomal proteases)

⭐ Cathepsins

Cathepsins are lysosomal proteases responsible for degrading proteins inside the lysosome.

Characteristics

Optimum pH: acidic (pH 5)
Many types: Cathepsin B, D, L, K, etc.
Important for:
- Protein turnover
- Collagen breakdown
- Antigen processing
- Bone resorption (Cathepsin K)

Clinical Correlation

Cathepsin deficiency → lysosomal storage disorders
Cathepsin overactivity → bone diseases, cancer invasion

⭐ 2. Ubiquitin–Proteasome Pathway (UPP)

The major pathway for degrading short-lived, abnormal, and regulatory proteins.

Where?

Cytoplasm & nucleus

Requires ATP

⭐ Steps in Ubiquitin–Proteasome Pathway

⭐ 1. Activation of Ubiquitin

Ubiquitin is activated by E1 enzyme (ATP-dependent).

⭐ 2. Conjugation

Ubiquitin is transferred to E2 enzyme.

⭐ 3. Ligation

E3 ligase attaches ubiquitin to Lys residues on target protein.

⭐ 4. Polyubiquitination

Protein is tagged with a chain of ubiquitin molecules.

⭐ 5. Degradation in Proteasome

Polyubiquitinated protein enters the 26S proteasome.
Proteasome cleaves it into small peptides.

⭐ Proteins Degraded by UPP

Misfolded proteins
Damaged proteins
Regulatory proteins (cyclins)
Transcription factors
Cancer-related proteins (p53, BRCA1)

⭐ Clinical Applications

Cancer therapy:
- Bortezomib inhibits proteasome → used in multiple myeloma
Neurodegenerative diseases:
- Faulty UPS → accumulation of misfolded proteins in Alzheimer’s, Parkinson’s
HPV E6/E7 proteins cause ubiquitin-mediated destruction of p53 and Rb

⭐ High-Yield Quick Revision

Meister cycle = GSH-dependent amino acid transport + GSH regeneration.
GGT is a marker of alcoholic liver disease.
Cathepsins = lysosomal proteases.
Ubiquitin pathway = ATP-dependent degradation of misfolded or short-lived proteins.
26S proteasome = main cytosolic degradation machinery.
Polyubiquitin tag directs proteins to proteasome.

⭐ Proteasomes

Proteasomes are large multi-enzyme complexes that degrade ubiquitin-tagged proteins inside the cytoplasm and nucleus.

⭐ Structure of Proteasome

The functional unit is the 26S proteasome.
Composed of:
- 20S core (catalytic barrel; protease activity)
- 19S regulatory caps (recognize ubiquitin tag, unfold proteins, feed them into core)

⭐ Functions

Degrades:
- Misfolded proteins
- Oxidatively damaged proteins
- Regulatory proteins (cyclins)
- Transcription factors
Maintains protein quality control.
Important in cell cycle regulation, immune responses, cancer cell survival.

⭐ Clinical Relevance

Bortezomib & Carfilzomib: proteasome inhibitors used in multiple myeloma.
Failure of proteasomal degradation → aggregation diseases
(Parkinson’s, Alzheimer’s, Huntington’s).

⭐ Inter-Organ Transport of Amino Acids

Amino acids move between tissues to meet metabolic demands.
Different organs prefer specific amino acids.

⭐ 1. Muscle

Muscle exports:

Alanine (major)
Glutamine (also significant)

Muscle uses amino acids for energy during fasting and exercise.

⭐ 2. Liver

Primary site of urea cycle.
Receives alanine from muscle → removes nitrogen → converts to urea.
Also receives glutamine from muscle & gut.

⭐ 3. Intestine

Uses glutamine as the preferred fuel.
Releases alanine into blood after metabolizing dietary amino acids.

⭐ 4. Kidney

Uses glutamine during acidosis → releases NH₄⁺ for acid excretion.
Produces serine via gluconeogenesis from glycine.

⭐ 5. Brain

Depends on glutamine ↔ glutamate cycling for neurotransmitter balance.

⭐ 6. Blood

Transports:

Free amino acids
Alanine (main nitrogen carrier from muscle to liver)
Glutamine (major carrier of ammonia)

⭐ High-Yield Summary

Alanine → liver (nitrogen transport, glucose production)
Glutamine → many tissues (fuel, nitrogen donor)
Muscle = major exporter
Liver = major receiver

⭐ Glucose–Alanine Cycle (Cahill Cycle)

The Glucose–Alanine cycle transfers nitrogen from muscle to liver and returns glucose to muscle.

It operates during:

Fasting
Prolonged exercise
Muscle protein breakdown
Conditions requiring glucose conservation

⭐ Steps of the Glucose–Alanine Cycle

⭐ 1. In Muscle

Muscle proteolysis → amino acids → release NH₃.
NH₃ + pyruvate → alanine (via alanine transaminase, ALT).
Alanine is released into blood.

⭐ 2. Transport to Liver

Alanine travels through blood to the liver.

⭐ 3. In Liver

Alanine → pyruvate + NH₃ (via ALT).
NH₃ enters urea cycle → converted to urea.
Pyruvate enters gluconeogenesis → forms glucose.

⭐ 4. Glucose Returned to Muscle

Liver releases glucose into blood.
Muscle uses this glucose for energy.

⭐ Functions of Glucose–Alanine Cycle

✔ 1. Transport of nitrogen

Carries nitrogen from muscle → liver safely as alanine.

✔ 2. Removal of toxic ammonia

Ammonia converted to urea in liver.

✔ 3. Fuel supply

Provides glucose back to muscle during fasting/exercise.

✔ 4. Supports gluconeogenesis

Pyruvate → glucose (especially during prolonged fasting).

⭐ Clinical Importance

Elevated ALT in serum indicates muscle or liver damage.
Overactive cycle occurs in catabolic states (burns, sepsis).
Important for survival during starvation.

⭐ High-Yield Exam Lines

Alanine is the major amino acid released from muscle during fasting.
Muscle uses alanine to send nitrogen → liver.
Liver uses alanine for gluconeogenesis + urea production.
The cycle links protein breakdown with glucose homeostasis.

⭐ Catabolism of Amino Acids

Amino acid catabolism involves two major processes:

Removal of nitrogen
Metabolism of the carbon skeleton

These processes occur mainly in the liver.

⭐ 1. Removal of Nitrogen

Amino acids first undergo one of the following:

a. Transamination

Transfer of amino group to α-ketoglutarate → forms glutamate.

b. Oxidative deamination

Glutamate releases NH₃ → free ammonia.

c. Non-oxidative deamination

Serine, threonine → NH₃ release without oxidation.

d. Decarboxylation

Produces amines (GABA, histamine, serotonin).

⭐ 2. Fate of Carbon Skeleton

After nitrogen removal, carbon skeletons enter major metabolic pathways as:

Pyruvate
Acetyl-CoA / Acetoacetate
α-Ketoglutarate
Succinyl-CoA
Fumarate
Oxaloacetate

⭐ Glucogenic Amino Acids

Produce glucose precursors (all except leucine and lysine).

⭐ Ketogenic Amino Acids

Leucine and Lysine (strictly ketogenic)
Produce acetyl-CoA / acetoacetate.

⭐ Formation of Ammonia

Ammonia (NH₃) is mainly formed during amino acid breakdown.
Because ammonia is toxic, it must be converted to urea.

⭐ Sources of Ammonia

⭐ 1. Oxidative Deamination

Enzyme: Glutamate dehydrogenase
Glutamate → α-ketoglutarate + NH₃
Occurs in liver mitochondria

⭐ 2. Oxidative Deamination of Amino Acids

Dehydratases produce NH₃ (e.g., serine, threonine).

⭐ 3. Intestinal Bacteria

Urease-producing bacteria liberate NH₃ from urea.
Largest extrahepatic source of ammonia.
Explains high NH₃ in liver failure.

⭐ 4. Amino Acid Oxidases

Produce NH₃ using FMN/FAD.

⭐ 5. Purine and Pyrimidine Metabolism

Deamination releases NH₃.

⭐ 6. Kidney

Glutaminase releases NH₃ to buffer urine.

⭐ Transport of Ammonia

Because free NH₃ is toxic, it moves between tissues as:

⭐ 1. Alanine (muscle → liver)

Via Glucose–Alanine cycle.

⭐ 2. Glutamine (all tissues → liver/kidney)

Glutamine carries two nitrogen atoms safely.

⭐ Transamination

Transamination is the first step of amino acid catabolism.

⭐ Definition

Transfer of an amino group from an amino acid → α-ketoglutarate
to form:

A new amino acid
A new keto acid

⭐ Enzyme

Aminotransferases / Transaminases

All require Pyridoxal phosphate (PLP)
→ Vitamin B6 derivative.

⭐ Important Transamination Reactions

⭐ 1. Alanine Transaminase (ALT)

Alanine + α-ketoglutarate

→ Pyruvate + Glutamate

ALT rises in liver injury.

⭐ 2. Aspartate Transaminase (AST)

Aspartate + α-ketoglutarate

→ Oxaloacetate + Glutamate

AST rises in cardiac + liver injury.

⭐ 3. Universal Amino Group Acceptor

→ α-Ketoglutarate
Forms glutamate.

⭐ Features of Transamination

Reversible
Does not release free ammonia
Occurs in cytosol & mitochondria
Not performed by:
- Lysine
- Threonine
- Proline
- Hydroxyproline

⭐ Functions of Transamination

Collects nitrogen as glutamate
Produces keto acids for energy
Transfers nitrogen to urea cycle via:
- Glutamate
- Aspartate

⭐ Clinical Relevance

ALT and AST are important liver function markers.
Vitamin B6 deficiency → ↓ transamination → neurological problems.

⭐ Oxidative Deamination

Oxidative deamination removes the amino group as free ammonia (NH₃) while oxidizing the amino acid.
This is the major pathway for liberating ammonia in the body.

⭐ Key Enzyme: Glutamate Dehydrogenase (GDH)

Location:

Mitochondria of liver and kidney

Reaction:

Glutamate + NAD⁺/NADP⁺

→ α-ketoglutarate + NH₃ + NADH/NADPH

Why glutamate?

Transamination reactions funnel amino groups from most amino acids onto α-ketoglutarate, forming glutamate.
Thus glutamate becomes the central collector of amino groups → oxidative deamination removes them.

⭐ Features of GDH

Uses either NAD⁺ or NADP⁺
Reaction is reversible
Activated by ADP, GDP (signals need for energy)
Inhibited by ATP, GTP (energy abundance)

⭐ Clinical Point

A defect in GDH regulation → hyperinsulinism-hyperammonemia syndrome
(Excess ammonia + recurrent hypoglycemia).

⭐ Non-Oxidative Deamination

These reactions remove ammonia without oxidation.

They occur mainly in amino acids containing hydroxyl or sulfur groups.

⭐ Enzymes

Serine dehydratase
Threonine dehydratase
Cysteine desulfhydrase

⭐ Examples of Reactions

1. Serine → Pyruvate + NH₃

Catalyzed by serine dehydratase.

2. Threonine → α-ketobutyrate + NH₃

Catalyzed by threonine dehydratase.

3. Cysteine → Pyruvate + NH₃ + H₂S

Catalyzed by cysteine desulfhydrase.

⭐ Features

PLP (Vitamin B6) dependent
No involvement of NAD⁺/NADP⁺
Occur mainly in liver

⭐ Disposal of Ammonia

Ammonia is highly neurotoxic, so the body must convert it into safe, non-toxic forms.

The major routes:

Urea Cycle (primary disposal mechanism)
Formation of glutamine
Formation of alanine
Excretion via kidney

Let's summarise them.

⭐ 1. Urea Cycle (Primary Disposal)

Occurs in liver (mitochondria + cytosol).

Converts NH₃ + CO₂ into urea, which is excreted by kidneys.

(Full urea cycle will be detailed separately in the next section.)

⭐ 2. Formation of Glutamine — Most Important Extrahepatic Pathway

⭐ Enzyme: Glutamine Synthetase

Glutamate + NH₃ + ATP → Glutamine

⭐ Importance

Glutamine carries two nitrogen atoms safely through blood.
Occurs in muscle, brain, and liver (periportal).

⭐ Uses of Glutamine

Transport NH₃ to liver
Fuel for kidney & intestine
Detoxification in brain
Precursor for nucleotide synthesis

⭐ 3. Formation of Alanine — Transport from Muscle to Liver

Through Glucose-Alanine Cycle:

Muscle: pyruvate + NH₃ → alanine
Alanine travels to liver
Liver: alanine → pyruvate + NH₃ → urea
Pyruvate → glucose → back to muscle

⭐ 4. Renal Ammonia Excretion

In kidneys, ammonia traps protons to excrete acid.

⭐ Enzyme: Glutaminase

Glutamine → Glutamate + NH₃

NH₃ + H⁺ → NH₄⁺ (excreted in urine)

⭐ During acidosis

Kidney produces more ammonia
Helps remove excess H⁺
Important in maintaining acid–base balance

⭐ 5. Minor Routes

Bacterial urease in gut produces NH₃—absorbed → detoxified by liver.
Purine/pyrimidine metabolism releases small amounts of NH₃.

⭐ High-Yield Summary

Oxidative deamination (GDH) liberates most ammonia.
Non-oxidative deamination: serine, threonine, cysteine.
Ammonia is disposed mainly via urea cycle, glutamine, and alanine.
Kidney disposes NH₄⁺ especially during acidosis.
Glutamine is the major carrier of ammonia in blood.
Alanine carries ammonia from muscle → liver.

⭐ UREA CYCLE (Ornithine Cycle)

The urea cycle converts toxic ammonia (NH₃) into non-toxic urea, which is excreted by the kidneys.

⭐ Site

Liver — only organ with complete cycle
Steps occur in mitochondria + cytosol

⭐ Purpose of the Urea Cycle

Remove ammonia, a potent neurotoxin
Convert nitrogen → urea
Regeneration of ornithine

⭐ STEPS OF THE UREA CYCLE

⭐ Step 1 (Mitochondria)

Formation of Carbamoyl Phosphate

Enzyme: Carbamoyl Phosphate Synthetase I (CPS-I)
Requires:

2 ATP
NH₃
CO₂
N-acetylglutamate (NAG) as obligatory activator

Product: Carbamoyl phosphate

⭐ Step 2 (Mitochondria)

Carbamoyl Phosphate + Ornithine → Citrulline

Enzyme: Ornithine Transcarbamoylase (OTC)
Citrulline enters cytosol.

⭐ Step 3 (Cytosol)

Citrulline + Aspartate → Argininosuccinate

Enzyme: Argininosuccinate Synthetase
Requires ATP

Aspartate provides the second nitrogen of urea.

⭐ Step 4 (Cytosol)

Argininosuccinate → Arginine + Fumarate

Enzyme: Argininosuccinate Lyase

Fumarate → TCA cycle (fumarate shuttle)

⭐ Step 5 (Cytosol)

Arginine → Ornithine + Urea

Enzyme: Arginase

Urea enters blood → excreted by kidney.
Ornithine returns to mitochondria.

⭐ Energy Requirement

Urea cycle consumes 4 high-energy bonds (3 ATP)
But fumarate → TCA produces some ATP → net cost slightly lower

⭐ Regulation of Urea Cycle

⭐ 1. N-Acetylglutamate (NAG)

Mandatory activator of CPS-I
Produced from glutamate + acetyl-CoA
Formation of NAG ↑ when amino acid catabolism ↑

⭐ 2. Enzyme induction

High protein diet or fasting increases transcription of urea cycle enzymes.

⭐ Clinical Importance

Urea cycle removes bulk of nitrogen
Liver failure → ↑ ammonia → hepatic encephalopathy

⭐ DISORDERS OF THE UREA CYCLE

All are autosomal recessive, except OTC deficiency (X-linked).

All cause:

Hyperammonemia
Lethargy
Poor feeding
Vomiting
Seizures
Cerebral edema
Respiratory alkalosis

Early presentation in newborns → life-threatening.

⭐ 1. Carbamoyl Phosphate Synthetase I (CPS-I) Deficiency

Type I Hyperammonemia
Severe ↑ NH₃
No carbamoyl phosphate formed

Labs:

↓ orotic acid
↓ citrulline
Very high ammonia

⭐ 2. Ornithine Transcarbamoylase (OTC) Deficiency

Most common UCD
X-linked
Carbamoyl phosphate builds up → enters pyrimidine pathway → ↑ orotic acid

Labs:

↑ Orotic acid (key marker)
↓ citrulline
Hyperammonemia
Normal blood glucose

⭐ 3. Argininosuccinate Synthetase Deficiency

Disease: Citrullinemia

Accumulation of citrulline

Labs:

↑ Citrulline (very high)
↑ ammonia

⭐ 4. Argininosuccinate Lyase Deficiency

Disease: Argininosuccinic aciduria

Accumulation of argininosuccinate

Features:

Brittle hair (trichorrhexis nodosa)
↑ ammonia
↑ argininosuccinate

⭐ 5. Arginase Deficiency

Disease: Argininemia

↑ arginine
Milder hyperammonemia
Spasticity, tremors, ataxia

Labs:

Very high arginine

⭐ General Laboratory Pattern in UCDs

High ammonia
Respiratory alkalosis
Specific amino acids elevated depending on block
No metabolic acidosis (unlike organic acidemias)

⭐ Treatment of Urea Cycle Disorders

⭐ Acute Management

Stop protein intake
Hemodialysis (rapid ammonia removal)
IV sodium benzoate / phenylacetate → nitrogen scavengers
IV arginine (except in arginase deficiency)

⭐ Chronic Management

Low protein diet
Benzoate/phenylbutyrate therapy
Oral arginine (depending on defect)
Liver transplantation (curative)

⭐ High-Yield Differences

Disorder	Marker	Amino Acid Elevated
CPS-I Deficiency	↓ orotic acid	↓ citrulline
OTC Deficiency	↑ orotic acid	↓ citrulline
Citrullinemia	Normal orotic acid	↑↑ citrulline
Argininosuccinate lyase deficiency	Normal orotic acid	↑ argininosuccinate
Arginase deficiency	Normal orotic acid	↑ arginine

⭐ Ultra-Short Revision

CPS-I needs NAG.
OTC deficiency → high orotic acid.
Citrullinemia → very high citrulline.
Argininosuccinic aciduria → hair abnormalities.
Arginase deficiency → spasticity + high arginine.
All cause hyperammonemia + respiratory alkalosis.

⭐ HEPATIC COMA (Hepatic Encephalopathy)

Hepatic coma results from failure of the liver to detoxify ammonia, leading to accumulation of NH₃ in blood and brain.

This is a LIFE-THREATENING complication of liver failure.

⭐ Causes

1. Liver failure

Acute fulminant hepatitis
Severe alcoholic hepatitis
Cirrhosis with portal hypertension

2. Portosystemic shunts

Blood bypasses liver → ammonia remains undetoxified

3. Precipitating factors

GI bleeding
High protein intake
Constipation
Diuretics → hypokalemia
Infections
Sedatives
Renal failure

⭐ Pathogenesis

⭐ 1. Ammonia Accumulation

Gut bacteria produce ammonia
Failing liver cannot convert ammonia → urea
NH₃ crosses blood–brain barrier

⭐ 2. Astrocyte swelling

Ammonia + glutamate → glutamine
Osmotic swelling of astrocytes → cerebral edema

⭐ 3. Neurotransmitter abnormalities

Increased GABAergic tone
Altered serotonin, glutamate pathways
“False neurotransmitters” accumulation

⭐ Clinical Features

Confusion, irritability
Personality changes
Flapping tremor (asterixis)
Disorientation, slurred speech
Drowsiness → stupor → coma
Fetor hepaticus (sweet musty smell)
Seizures in severe cases

⭐ Investigations

Very high blood ammonia level
EEG: triphasic waves
LFT abnormalities
Precipitating factor identification (K⁺, infection, bleeding)

⭐ Management

1. Reduce ammonia production

Lactulose: converts NH₃ → NH₄⁺, increases stool frequency
Rifaximin: reduces ammonia-producing gut bacteria

2. Correct precipitating factors

Treat GI bleed, infection, dehydration
Stop sedatives, adjust diuretics

3. Diet

Low protein initially
Vegetable protein preferred later

4. Severe cases

ICU care
Mechanical ventilation
Liver transplantation

⭐ High-Yield Lines

Ammonia accumulation is the main cause.
Ammonia → glutamine → astrocyte swelling → cerebral edema.
Lactulose is the drug of choice.
Asterixis = classic sign.

⭐ BLOOD UREA

Urea is the major end product of nitrogen metabolism, produced exclusively by the liver through the urea cycle.

It is excreted mainly by the kidneys.

⭐ Normal Values

Blood Urea Nitrogen (BUN): 7–20 mg/dL
Serum urea: 20–40 mg/dL (depending on lab standards)

⭐ Factors Affecting Blood Urea

⭐ 1. Increased Blood Urea

⭐ a. Pre-renal causes (high BUN/Creatinine ratio)

Dehydration
Shock
Heart failure
High protein diet
GI bleeding (digested blood → amines → urea)
Corticosteroid therapy

⭐ b. Renal causes

Acute or chronic renal failure
Glomerulonephritis
Tubular necrosis

⭐ c. Post-renal causes

Obstruction (stones, prostate enlargement)

⭐ 2. Decreased Blood Urea

Severe liver disease (urea cycle suppressed)
Low protein intake
Pregnancy (increased plasma volume)
SIADH

⭐ Clinical Uses of Blood Urea

Marker of renal function
Assessment of hydration status
Differentiates pre-renal vs renal azotemia
Monitors dialysis effectiveness
Elevated in GI bleed due to increased protein absorption

⭐ BUN : Creatinine Ratio

⭐ Normal: 10–15 : 1

Condition	BUN:Cr Ratio	Explanation
Pre-renal azotemia	>20:1	Increased urea reabsorption
Renal failure	10–15:1 (normal)	Both impaired
Post-renal	Variable	Obstruction

⭐ High-Yield Points

Urea depends on liver synthesis, creatinine does not.
Low urea = severe hepatic failure or low protein intake.
Urea cross BBB → contributes to encephalopathy only when liver fails to detoxify ammonia.
BUN rises faster in dehydration than creatinine.

⭐ ONE-CARBON COMPOUNDS (One-Carbon Units)

One-carbon units are single-carbon fragments transferred between molecules during amino acid, nucleotide, and methylation reactions.

These 1-carbon units are carried mainly by:

⭐ Tetrahydrofolate (THF) – the primary carrier

⭐ S-adenosylmethionine (SAM) – the strongest methyl donor

⭐ Vitamin B₁₂ – accepts/transfers methyl groups in selected reactions

⭐ Types of One-Carbon Units Carried by THF

THF carries one-carbon groups in various oxidation states:

Formyl (–CHO)
Formimino (–CH=NH)
Methylene (–CH₂–)
Methenyl (–CH=)
Methyl (–CH₃)
Hydroxymethyl (–CH₂OH)

These interchangeable forms allow THF to participate in a wide range of biosynthetic reactions.

⭐ GENERATION OF ONE-CARBON GROUPS

One-carbon units come from amino acid metabolism.

⭐ 1. Serine → Glycine

Major source
Enzyme: Serine hydroxymethyltransferase
Produces: Methylene-THF

⭐ 2. Glycine cleavage system

Glycine → CO₂ + NH₃ + 1-carbon unit
Produces: Methylene-THF

⭐ 3. Histidine metabolism

Formiminoglutamate (FIGLU) → Glutamate
Produces: Formimino-THF

⭐ 4. Tryptophan metabolism

Provides formyl groups
Produces: Formyl-THF

⭐ 5. Choline metabolism

Provides methyl groups
Produces: Methyl-THF

⭐ 6. Formaldehyde

Detected in some metabolic reactions
Converted → methylene-THF

⭐ 7. Dimethylglycine / Sarcosine

Produce methyl groups during oxidation
Contribute to methyl-THF pool

⭐ Summary: Sources of One-Carbon Units

Source Amino Acid	One-Carbon Group Produced
Serine	Methylene-THF
Glycine	Methylene-THF
Histidine	Formimino-THF
Tryptophan	Formyl-THF
Choline	Methyl-THF

⭐ UTILIZATION OF ONE-CARBON GROUPS

One-carbon units are used in many essential biochemical pathways.

⭐ 1. Purine Synthesis

THF donates:

Formyl-THF → For C-2
Formyl-THF → For C-8

Required for synthesis of AMP & GMP.

⭐ 2. Pyrimidine (Thymidine) Synthesis

Methylene-THF → donates CH₂ to dUMP → dTMP (thymidine)
Enzyme: Thymidylate synthase
Crucial for DNA synthesis

⭐ 3. Methionine Synthesis

Vitamin B₁₂ + THF participate:

Homocysteine + methyl-THF → Methionine
Methionine → SAM (universal methyl donor)

Defects → homocystinuria, megaloblastic anemia.

⭐ 4. Methylation Reactions (via SAM)

SAM donates methyl groups to:

DNA methylation
RNA methylation
Phospholipids (phosphatidylethanolamine → phosphatidylcholine)
Creatine synthesis
Adrenaline synthesis
Melatonin synthesis

SAM is the most powerful methyl donor.

⭐ 5. Conversion Between Forms of One-Carbon Units

THF interconverts between forms:

Methylene ↔ Methenyl ↔ Formyl
Reversible transformations allow flexible use

Exception:
Methyl-THF → irreversible conversion from methylene-THF
(“Methyl-folate trap” in B₁₂ deficiency)

⭐ 6. Detoxification and Amino Acid Metabolism

Histidine → glutamate (requires THF)
Degradation of glycine & serine
Interconversion of amino acids

⭐ THE METHYL-FOLATE TRAP (Clinical Importance)

In Vitamin B₁₂ deficiency:

Methyl-THF cannot donate methyl group → methionine
THF becomes “trapped” as methyl-THF
Functional folate deficiency develops
Leads to megaloblastic anemia

Folate supplementation alone will NOT correct neurological symptoms.

⭐ High-Yield Summary

THF carries one-carbon units in different oxidation states.
Major sources: serine, glycine, histidine, tryptophan, choline.
Major uses: purine synthesis, thymidine synthesis, methionine/SAM formation.
SAM is the universal methyl donor.
B₁₂ deficiency → methyl-folate trap.

⭐ FACTS TO REMEMBER — WHOLE CHAPTER

⭐ Digestion & Absorption

Pepsin is an endopeptidase activated by HCl.
Pancreatic proteases are released as zymogens; trypsin activates all others.
PEPT1 absorbs di- and tripeptides (H⁺-dependent).
Most bowel protein absorption is via dipeptides > free amino acids.

⭐ Meister (γ-Glutamyl) Cycle

Uses glutathione (GSH) to transport amino acids into cells.
GGT is the key enzyme; elevated in alcoholic liver disease.
Cycle regenerates glutathione at the expense of ATP.

⭐ Intracellular Protein Degradation

Lysosomes degrade long-lived proteins → via cathepsins (acidic pH).
Ubiquitin–proteasome system degrades short-lived / damaged proteins.

⭐ Ubiquitin–Proteasome Pathway

Requires ATP.
Uses three enzymes: E1 (activation), E2 (conjugation), E3 (ligation).
Polyubiquitin tag targets proteins for 26S proteasome.
Proteasome inhibitors (e.g., Bortezomib) used in multiple myeloma.

⭐ Inter-Organ Transport of Amino Acids

Alanine = major nitrogen carrier from muscle → liver.
Glutamine = major carrier of ammonia from tissues.
Intestine uses glutamine as its main fuel.

⭐ Glucose–Alanine Cycle

Muscle: amino acids → NH₃ → alanine.
Liver: alanine → pyruvate + NH₃ → urea.
Pyruvate → glucose, returned to muscle.
Operates in fasting & exercise.

⭐ Transamination

ALT & AST require PLP (vitamin B6).
α-Ketoglutarate is the universal amino group acceptor.
Transamination does not produce free ammonia.
Lysine, threonine, proline do not undergo transamination.

⭐ Oxidative Deamination

Major enzyme: Glutamate dehydrogenase (GDH).
Occurs in liver mitochondria.
Releases free NH₃ from glutamate.
Uses NAD⁺ or NADP⁺.

⭐ Non-Oxidative Deamination

Serine & threonine undergo dehydration to release NH₃.
Requires pyridoxal phosphate (PLP).

⭐ Sources of Ammonia

Oxidative deamination (glutamate → NH₃).
Intestinal bacteria (largest external source).
Amino acid oxidases.
Purine/pyrimidine catabolism.
Renal glutaminase.

⭐ Transport of Ammonia

Glutamine carries 2 nitrogen atoms (most important).
Alanine carries nitrogen from muscle → liver.

⭐ Urea Cycle (Ornithine Cycle)

Occurs in liver (mitochondria + cytosol).
First step enzyme: CPS-I (requires N-acetylglutamate, NAG).
Provides 2 nitrogen atoms:
- One from ammonia
- One from aspartate
Fumarate links urea cycle with TCA cycle.

⭐ Regulation

NAG is obligatory activator of CPS-I.
High protein → increases urea cycle enzyme synthesis.

⭐ Urea Cycle Disorders (UCDs)

All autosomal recessive except OTC deficiency (X-linked).
All cause hyperammonemia + respiratory alkalosis.
OTC deficiency → ↑ orotic acid (due to pyrimidine overflow).
Citrullinemia → ↑ citrulline.
Argininosuccinic aciduria → ↑ argininosuccinate + brittle hair.
Arginase deficiency → ↑ arginine, spasticity with milder ammonia rise.
CPS-I deficiency → ↓ orotic acid.

⭐ Treatment Overview

Stop protein; give benzoate/phenylbutyrate (nitrogen scavengers).
Arginine therapy (except in arginase deficiency).
Dialysis for severe hyperammonemia.
Liver transplant = curative.

⭐ Hepatic Coma

Caused by ammonia accumulation due to liver failure.
Ammonia → glutamine → astrocyte swelling → cerebral edema.
Signs: asterixis, confusion, fetor hepaticus.
Treatment: lactulose, rifaximin, remove precipitating factors.

⭐ Blood Urea

Increased in renal failure, dehydration, GI bleed.
Decreased in liver failure (urea cycle impaired).
High BUN:Cr ratio (>20) = pre-renal azotemia.

⭐ One-Carbon Metabolism (Folate Cycle)

THF carries one-carbon units → formyl, methenyl, methylene, methyl.
Major sources: serine, glycine, histidine, tryptophan, choline.
Used for purine synthesis, dTMP synthesis, methionine synthesis (with B12).
SAM = strongest methyl donor.
B12 deficiency → methyl-folate trap → megaloblastic anemia.

⭐ Super-High-Yield Lines

Glutamate is the central amino acid in nitrogen metabolism.
Glutamine is the major ammonia transport form.
Alanine is the major fasting muscle export.
CPS-I is mitochondrial; CPS-II (pyrimidine synthesis) is cytosolic.
Only the liver can produce significant quantities of urea.
Hyperammonemia causes respiratory alkalosis, not acidosis.
SAM donates methyl groups for creatine, adrenaline, phosphatidylcholine.
FIGLU excretion ↑ in folate deficiency.

⭐ FAQs — General Amino Acid Metabolism (Complete Chapter)

1. What is the first step in amino acid catabolism?

Transamination, where amino groups are transferred to α-ketoglutarate to form glutamate.

2. Which vitamin is required for all transamination reactions?

Vitamin B6 (Pyridoxal phosphate, PLP).

3. Which amino acids do NOT undergo transamination?

Lysine, threonine, proline, hydroxyproline.

4. What is the main purpose of transamination?

To funnel nitrogen to glutamate, which can undergo oxidative deamination.

5. What enzyme performs oxidative deamination?

Glutamate dehydrogenase (GDH) in the liver mitochondria.

6. What is the main product of oxidative deamination?

Free ammonia (NH₃) + α-ketoglutarate.

7. Name important sources of ammonia in the body.

Oxidative deamination (glutamate)
Intestinal bacteria (urease)
Purine/pyrimidine metabolism
Amino acid oxidases
Renal glutaminase

8. How is ammonia transported in blood?

As glutamine and alanine.

9. Why is ammonia toxic to the brain?

Because it forms excess glutamine, causing astrocyte swelling → cerebral edema.

10. What is the major detoxification pathway for ammonia?

The urea cycle in the liver.

11. Which enzyme starts the urea cycle?

Carbamoyl phosphate synthetase I (CPS-I).

12. What is the obligatory activator of CPS-I?

N-Acetylglutamate (NAG).

13. Where is the urea cycle located?

Partly in mitochondria, partly in cytosol.

14. Which amino acid donates the second nitrogen of urea?

Aspartate.

15. Which step of the urea cycle is defective in OTC deficiency?

Conversion of carbamoyl phosphate + ornithine → citrulline.

16. What is the biochemical hallmark of OTC deficiency?

High orotic acid in urine.

17. What amino acid is elevated in citrullinemia?

Citrulline (very high).

18. Which urea cycle disorder presents with brittle hair?

Argininosuccinic aciduria.

19. Which disorder shows very high arginine levels?

Arginase deficiency.

20. What acid–base disturbance occurs in urea cycle disorders?

Respiratory alkalosis (hyperventilation due to cerebral edema).

21. What is the role of glutamine synthetase?

Converts NH₃ + glutamate → glutamine, a safe transport form.

22. What is the purpose of the Glucose–Alanine cycle?

To carry muscle nitrogen → liver, while providing glucose back to muscle.

23. What is the major nitrogen donor in biosynthetic reactions?

Glutamine.

24. What is the major nitrogen acceptor in transamination?

α-Ketoglutarate → converts to glutamate.

25. What is the γ-glutamyl/Meister cycle used for?

Transport of amino acids into cells using glutathione.

26. Which enzyme is elevated in alcoholic liver disease?

GGT (from Meister cycle).

27. What is the role of proteasomes?

Degrade ubiquitin-tagged proteins using ATP.

28. What is the difference between lysosomal & proteasomal degradation?

Lysosomal → long-lived + extracellular proteins
Proteasomal → short-lived + misfolded proteins (ATP-dependent)

29. What is the universal methyl donor in the body?

S-Adenosylmethionine (SAM).

30. Which vitamin regenerates methyl-THF?

Vitamin B12.

31. What happens in methyl-folate trap?

Without B12, methyl-THF cannot convert to THF → functional folate deficiency.

32. What are the major uses of one-carbon units?

Purine synthesis
Thymidine synthesis (dTMP)
Methionine/SAM synthesis
Amino acid interconversion

33. What is FIGLU, and when is it elevated?

Formiminoglutamate → elevated in folate deficiency.

34. What causes hepatic coma?

Failure to detoxify ammonia → NH₃ buildup → astrocyte swelling → coma.

35. What are clinical signs of hepatic encephalopathy?

Asterixis, confusion, fetor hepaticus, altered consciousness.

36. What drug converts NH₃ → NH₄⁺ in the intestine?

Lactulose.

37. What are nitrogen scavenger drugs?

Sodium benzoate, sodium phenylbutyrate.

38. What is the normal BUN:Creatinine ratio?

10–15 : 1.

39. What causes high BUN with normal creatinine?

Answer: C

24. Methyl-folate trap occurs in deficiency of:

A. Folate only
B. Pyridoxine
C. Vitamin B12
D. Thiamine

Answer: C

25. FIGLU excretion increases in:

A. B12 deficiency only
B. Folate deficiency
C. Niacin deficiency
D. Riboflavin deficiency

Answer: B

⭐ Clinical Problems — General Amino Acid Metabolism (Complete Chapter)

1. Newborn with vomiting, lethargy & respiratory alkalosis

A 2-day-old newborn develops poor feeding, lethargy, vomiting, and rapid breathing. Labs show:

Very high ammonia
Low citrulline
Normal orotic acid

Diagnosis:

CPS-I deficiency

Explanation:

No carbamoyl phosphate formed → ↓ citrulline + no orotic acid buildup.

2. Newborn with hyperammonemia + very high orotic acid

A male infant becomes irritable, starts vomiting, and develops seizures on day 3. Labs show:

Very high ammonia
Very high orotic acid
Low citrulline

Diagnosis:

OTC deficiency (X-linked)

Explanation:

Excess carbamoyl phosphate enters pyrimidine pathway → ↑ orotic acid.

3. Infant with brittle hair and high ammonia

A 4-month-old has failure to thrive, seizures, and hair that breaks easily. Labs:

High ammonia
High argininosuccinate

Diagnosis:

Argininosuccinic aciduria (Argininosuccinate lyase deficiency)

Explanation:

Brittle hair (trichorrhexis nodosa) is classic.

4. Child with spasticity and high arginine

A 6-year-old has progressive spasticity, tremors, and delayed development. Labs:

High arginine
Mild ammonia elevation

BUN: 60 mg/dL
Creatinine: normal

Diagnosis:

Pre-renal azotemia

Mechanism:

Water reabsorption increases urea reabsorption, creatinine unchanged.

20. Low urea with high bilirubin

A patient with chronic liver disease has:

Very low serum urea
Elevated ammonia
High bilirubin

Diagnosis:

Liver failure

Mechanism:

Urea cycle is impaired → low urea + high ammonia.

⭐ Viva Voce — General Amino Acid Metabolism

1. What is the first step in amino acid catabolism?

Transamination.

2. Name the coenzyme required for transamination.

Pyridoxal phosphate (Vitamin B6).

3. Which amino acids do NOT undergo transamination?

Lysine, threonine, proline, hydroxyproline.

4. What is the main acceptor of amino groups in transamination?

α-Ketoglutarate.

5. What enzyme catalyzes oxidative deamination?

Glutamate dehydrogenase (GDH).

6. Where does oxidative deamination occur?

Mitochondria (mainly liver).

7. What are the products of oxidative deamination of glutamate?

α-Ketoglutarate and free ammonia (NH₃).

8. Name the major carriers of ammonia in blood.

Glutamine and alanine.

9. Why is ammonia toxic?

It forms excess glutamine in the brain → astrocyte swelling → cerebral edema.

10. Where does the urea cycle occur?

In the liver — partly mitochondria, partly cytosol.

11. What is the rate-limiting enzyme of the urea cycle?

Carbamoyl phosphate synthetase I (CPS-I).

12. What activates CPS-I?

N-acetylglutamate (NAG).

13. What are the two nitrogen sources of urea?

Ammonia and aspartate.

14. Which urea cycle disorder is X-linked?

Ornithine Transcarbamoylase (OTC) deficiency.

15. What is the biochemical hallmark of OTC deficiency?

High orotic acid in urine.

16. What is the hallmark of citrullinemia?

Very high citrulline in blood.

17. What is the hallmark of argininosuccinic aciduria?

High argininosuccinate + brittle hair.

18. What is the hallmark of arginase deficiency?

High arginine + spasticity with mild hyperammonemia.

19. What acid–base disturbance occurs in hyperammonemia?

Respiratory alkalosis.

20. What is the treatment of hepatic encephalopathy?

Lactulose + rifaximin + treat precipitating causes.

21. What is the Glucose–Alanine cycle?

Alanine carries nitrogen from muscle to liver, where it is converted to urea; pyruvate returns as glucose.

22. What is the role of glutamine synthetase?

Converts NH₃ to glutamine for safe transport.

23. What is the role of glutaminase in kidney?

Produces ammonia to excrete H⁺ as NH₄⁺, especially during acidosis.

24. What is GGT, and what does it indicate clinically?

A γ-glutamyl enzyme; elevated in alcoholic liver disease.

25. What is the function of the proteasome?

Degrades ubiquitin-tagged proteins using ATP.

26. What is the universal methyl donor?

S-adenosylmethionine (SAM).

27. Which enzyme regenerates methionine from homocysteine?

Methionine synthase (requires Vitamin B12).

28. What is the methyl-folate trap?

In B12 deficiency, methyl-THF cannot convert to THF → functional folate deficiency.

29. What is FIGLU, and what does it indicate?

Formiminoglutamate. Increased excretion indicates folate deficiency.

30. What is the role of THF?

Carrier of one-carbon units in various oxidation states.

31. What are the major one-carbon donors?

Serine, glycine, histidine, tryptophan, choline.

32. What is the major use of methylene-THF?

Conversion of dUMP → dTMP (thymidine).

33. Why does liver failure cause low urea?

Urea cycle does not function → decreased urea synthesis.

34. What is the normal BUN:Creatinine ratio?

10–15 : 1.

35. What causes a high BUN:Cr ratio?

Pre-renal causes like dehydration, GI bleed.

36. What are the effects of valproate on ammonia metabolism?

Inhibits CPS-I → hyperammonemia.

37. Name the two main sites of amino acid absorption.

Jejunum and ileum.

38. Which peptide transporter absorbs di- and tripeptides?

PEPT-1 (H⁺-dependent).

39. What are cathepsins?

Lysosomal proteases for degrading long-lived proteins.

40. Which organ uses glutamine as a major fuel source?

Intestine.

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General Amino Acid Metabolism (Urea Cycle, One Carbon Metabolism)

Topic Overview

⭐ General Amino Acid Metabolism

⭐ Digestion of Proteins

⭐ 1. Digestion in the Stomach

a. Hydrochloric Acid (HCl)

b. Pepsin

c. Product of gastric digestion

⭐ 2. Digestion in the Small Intestine

a. Hormonal Regulation

⭐ b. Pancreatic Proteases (Released as zymogens)

⭐ c. Intestinal Enzymes

⭐ Products of Digestion

⭐ Absorption of Amino Acids

⭐ 1. Absorption of Free Amino Acids

a. Na⁺-Dependent Transporters

b. Na⁺-Independent Transporters

⭐ 2. Absorption of Dipeptides & Tripeptides

PEPT1 Transporter

⭐ 3. Clinical Correlations

a. Cystinuria

b. Hartnup Disease

c. Pancreatic insufficiency

⭐ High-Yield Summary

⭐ Meister Cycle (γ-Glutamyl Cycle)

⭐ Key Components

⭐ Steps of Meister Cycle

1. γ-Glutamyl Transpeptidase (GGT) Reaction

2. Transport Into Cell

3. Hydrolysis Inside Cell

4. ATP-Dependent Recycling

⭐ Functions of the Meister Cycle

⭐ Clinical Note

⭐ Intracellular Protein Degradation

⭐ 1. Lysosomal Protein Degradation

Key Features

⭐ Cathepsins

Characteristics

Clinical Correlation

⭐ 2. Ubiquitin–Proteasome Pathway (UPP)

Where?

Requires ATP

⭐ Steps in Ubiquitin–Proteasome Pathway

⭐ 1. Activation of Ubiquitin

⭐ 2. Conjugation

⭐ 3. Ligation

⭐ 4. Polyubiquitination

⭐ 5. Degradation in Proteasome

⭐ Proteins Degraded by UPP

⭐ Clinical Applications

⭐ High-Yield Quick Revision

⭐ Proteasomes

⭐ Structure of Proteasome

⭐ Functions

⭐ Clinical Relevance

⭐ Inter-Organ Transport of Amino Acids

⭐ 1. Muscle

⭐ 2. Liver

⭐ 3. Intestine

⭐ 4. Kidney

⭐ 5. Brain

⭐ 6. Blood

⭐ High-Yield Summary

⭐ Glucose–Alanine Cycle (Cahill Cycle)

⭐ Steps of the Glucose–Alanine Cycle

⭐ 1. In Muscle

⭐ 2. Transport to Liver

⭐ 3. In Liver

⭐ 4. Glucose Returned to Muscle

⭐ Functions of Glucose–Alanine Cycle

✔ 1. Transport of nitrogen

✔ 2. Removal of toxic ammonia

✔ 3. Fuel supply

✔ 4. Supports gluconeogenesis

⭐ Clinical Importance

⭐ High-Yield Exam Lines

⭐ Catabolism of Amino Acids

⭐ 1. Removal of Nitrogen

a. Transamination

b. Oxidative deamination