PHRM246 Amino Acid Metabolism

Dynamics of Protein and Amino Acid Metabolism

• Dietary proteins undergo digestion to yield amino acids.
• Amino acids are transported through the blood to cells for protein synthesis.
• Proteins are degraded in proteasomes, tagged with ubiquitin for identification.

Digestion of Proteins

• Occurs in the stomach via pepsinogen (activated to pepsin at pH 2) and enteropeptidase.
• In the small intestine, trypsinogen activates to trypsin, which cleaves several zymogens:
  • Chymotrypsinogen to chymotrypsin
  • Proelastase to elastase
  • Procarboxypeptidase to carboxypeptidase.
• Aminopeptidases aid in digestion from intestinal epithelia.

Amino Acid Transport and Absorption

• Amino acids and oligopeptides are absorbed in the intestinal lumen.
• Transport proteins and peptidases facilitate absorption into the bloodstream.

Incorporation of Ammonium (NH4+)

• Ammonium ions combine with bicarbonate and ATP to form carbamoyl phosphate via Carbamoyl Phosphate Synthase I (CPS-I).
• In the mitochondria, α-ketoglutarate and NH4+ can yield glutamate through dehydrogenase mechanisms.
• Glutamate can further form glutamine through Glutamine Synthase.

Biosynthesis of Amino Acids

• Transamination processes interchange amino acids and α-keto acids, utilizing pyridoxal phosphate (PLP) for conversion.
• Enzymes like the alanine and aspartate transferases are critical for assessing liver health.

Classification of Amino Acids

• Essential Amino Acids: Cannot be synthesized, must be obtained from diet (e.g., arginine, lysine, methionine).
• Non-Essential Amino Acids: Can be synthesized in the body from α-keto acids (e.g., alanine, glutamine).
• Glucogenic Amino Acids: Can be converted into glucose precursors.
• Ketogenic Amino Acids: Converted into acetyl CoA or acetoacetyl CoA.

Urea Cycle and Ammonium Metabolism

• Primarily occurs in the liver; excretion by kidneys removes excess ammonia.
• Deficiencies in urea cycle enzymes lead to hyperammonemia and neurological issues in neonates.
• Elevated blood urea nitrogen (BUN) indicates amino acid catabolism and kidney function.

Formation and Role of Nitric Oxide

• Synthesized from arginine via nitric oxide synthase and is crucial for vasodilation.
• Implicated in various physiological processes and therapeutic applications (e.g., sildenafil).

Conversion Pathways for Amino Acids

• Conversion from serine to glycine is facilitated by serine hydroxymethyltransferase, a key step in purine and heme biosynthesis.
• Sarcosine, a derivative of glycine, is studied as a potential prostate cancer biomarker.

Important Enzymes and Processes

• Glutamate decarboxylase converts glutamate to gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter.
• Urea formation involves multiple enzymatic steps, converting ammonia into urea for detoxification and excretion.### B12-Dependent Pathways and Amino Acids
• Homocysteine, derived from methionine, can lead to serious health issues when elevated, including cardiovascular disease.
• Homocysteinuria results from cystathionine beta-synthase deficiency, presenting with dislocated lenses, mental retardation, and osteoporosis.
• Methionine metabolism involves the conversion of methionine to S-adenosyl methionine (SAM), a key methyl donor in biochemical reactions.

Polyamine Biosynthesis

• Polyamines, such as spermidine and spermine, are found in all living cells and bind nucleic acids, though their exact roles remain unclear.
• Ornithine decarboxylase is essential for polyamine biosynthesis and can be inhibited by a-Difluoromethyl-ornithine (DFMO) for treating specific infections.

Creatine and Creatinine

• Creatine is a dietary supplement used for athletic performance enhancement, while creatinine is a waste product measurable in urine, reflecting muscle mass.
• The creatinine clearance test assesses kidney function by comparing urine and blood creatinine levels, crucial for drug dosing in patients with renal impairment.

Histidine Metabolism and Histamine

• Histamine is formed from histidine via histidine decarboxylase and is released by mast cells during allergic responses.
• H1 and H2 histamine receptors are targeted by various medications: H1 blockers (like Diphenhydramine) and H2 blockers (like Cimetidine), affecting allergy and gastric acid secretion.

Phenylalanine and Tyrosine

• Phenylalanine, an essential amino acid, is converted into tyrosine in the body, which is considered non-essential despite being derived from phenylalanine.
• Phenylketonuria (PKU) occurs due to phenylalanine hydroxylase deficiency, leading to severe developmental issues; newborn screening for PKU has been mandated.

Catecholamine Biosynthesis

• Catecholamines such as dopamine, norepinephrine, and epinephrine are synthesized from tyrosine and play critical roles in the nervous system.
• L-DOPA is used in the treatment of Parkinson's disease to replenish lost dopamine in the brain, aided by carbidopa to enhance effectiveness.

Tyramine and MAO Inhibitors

• Tyramine can trigger a hypertensive crisis in individuals on monoamine oxidase (MAO) inhibitors due to increased norepinephrine release.

Catechol-O-Methyl Transferase (COMT)

• COMT terminates catecholamine activity in the cytoplasm.
• Active catecholamines are converted into inactive metabolites by COMT, alongside MAO.
• COMT inhibitors, such as tolcapone, are beneficial for treating Parkinson’s disease.

Homogentisic Acid Formation

• Transamination process converts tyrosine into p-hydroxyphenylpyruvate.
• Homogentisate dioxygenase deficiency leads to alkaptonuria, a condition characterized by dark urine due to oxidation of homogentisic acid.
• Individuals are typically asymptomatic during childhood but may develop arthritis in adulthood.

Melanin Formation

• Tyr hydroxylase catalyzes the conversion of tyrosine to DOPA, which further transforms into melanin.
• Melanin serves as a protective pigment in skin, eyes, and hair against sunlight.
• Albinism results from a genetic deficiency of tyrosinase, critical for melanin synthesis.

Tryptophan Metabolism: Serotonin Formation

• Tryptophan is converted to serotonin (5-hydroxytryptamine, 5-HT) via hydroxylation and decarboxylation processes.

Serotonin

• Serotonin functions as a neurotransmitter and influences mood, sleep, and appetite in the brain.
• Found in platelets, serotonin aids in aggregation and vasoconstriction.
• Major storage site of serotonin is within enterochromaffin cells in the gastrointestinal tract.
• Therapeutic drugs targeting serotonin include SSRIs for depression, alongside treatments for migraine, schizophrenia, and obsessive-compulsive disorders.
• Some hallucinogens, like LSD, act as serotonin agonists, influencing mood and perception.

L-Tryptophan

• L-Tryptophan, a food supplement, is associated with serotonin enhancement but is linked to Eosinophilia-myalgia syndrome (EMS) with symptoms like muscle pain, swelling, and rashes due to impurities leading to hundreds of cases and several fatalities.

Serotonin Metabolism: 5-HIAA

• 5-Hydroxyindole acetic acid (5-HIAA) is a urinary metabolite of serotonin.
• Carcinoid tumors result in excessive 5-HIAA excretion, indicating the presence of malignant gastrointestinal tumors.

Serotonin Metabolism: Melatonin

• Melatonin, synthesized primarily in the pineal gland, controls sleep cycles and is influenced by light.
• Melatonin can induce skin lightening and suppress ovarian function, with potential uses in treating sleep disorders.

Tryptophan Metabolism: Nicotinic Acid Biosynthesis

• Tryptophan undergoes several steps to form nicotinic acid (Niacin), an essential metabolite linked to energy metabolism and cellular function.
• Niacin is crucial for the synthesis of nicotinamide adenine dinucleotide (NAD), a key coenzyme in metabolic processes.