Conversion of Amino Acids to Specialized N-containing Compounds
Amino acids (a.a) are precursors of many nitrogen-containing compounds and serve as the building blocks of proteins.
Porphyrins
Definition: Porphyrins are cyclic compounds that typically bind metal ions, often Fe+2 and Fe+3.
Metalloporphyrin in Humans: The metalloporphyrin in humans is heme, which serves as a prosthetic group for several important proteins, including:
Hemoglobin
Myoglobin
Cytochromes
Catalase
Tryptophan pyrrolase
Heme Composition: Heme contains one ferrous ion (Fe+2) coordinated at the center of the porphyrin ring.
Heme Turnover: Approximately 6 – 7 grams of heme is synthesized and degraded daily.
Structure of Porphyrins:
Consists of a ring structure formed by four pyrrole rings interconnected by methylenyl bridges.
Varying side chains attached to the pyrrole rings lead to the classification of porphyrins into four types: I, II, III, and IV.
Biosynthesis of Porphyrins
The liver is the major site for heme biosynthesis.
Location of Reactions:
Initial and final three reactions occur in the mitochondria, while the other reactions take place in the cytosol.
Formation of δ-Amino Levulinic Acid (ALA)
Precursor Composition: All carbons and nitrogens of the porphyrin compound are derived from glycine and succinyl-CoA.
Catalyzing Enzyme: The synthesis of ALA is catalyzed by ALA synthase, marking the rate-limiting step in porphyrin biosynthesis.
Inhibition: ALA synthase activity is inhibited by Hemin.
Formation of Porphobilinogen
Two molecules of ALA condense via the enzyme amino levulinic acid dehydrase to form porphobilinogen.
Formation of Uroporphyrinogen
Process: Four molecules of porphobilinogen condense to produce uroporphyrin III.
Formation of Heme
Uroporphyrin III undergoes several decarboxylation steps leading to the synthesis of heme.
Degradation of Heme
Lifespan of Red Blood Cells (RBCs): RBCs have a lifespan of 120 days; they are phagocytosed by the liver, spleen, and macrophages, where degradation occurs through the reticulo-endothelial system (RE).
Formation of Bilirubin
Catalytic Enzyme: The microsomal heme oxygenase enzyme facilitates the first reaction in heme degradation, adding -OH to the methylene bridge.
Products of Reaction: Carbon monoxide (CO) and ferric ion (Fe+3) are released, yielding biliverdin, which is further reduced to bilirubin.
Uptake of Bilirubin by the Liver
Solubility Characteristics: Bilirubin is poorly soluble in water, thus it is transported in the bloodstream by complexing with albumin before being taken up by hepatocytes.
Formation of Bilirubin Diglucuronide
In hepatocytes, bilirubin's solubility is enhanced by the addition of two molecules of glucuronic acid through the action of the enzyme bilirubin glucuronyl transferase, utilizing UDP-glucuronic acid.
Excretion of Bilirubin into Bile
Bilirubin diglucuronide is actively transported into bile for excretion.
Formation of Urobillins in the Intestine
In the gut, bilirubin diglucuronide undergoes hydrolysis and reduction mediated by bacterial enzymes to produce urobilinogen.
Jaundice
Definition: Jaundice presents as a yellow coloration of the skin and sclera due to elevated bilirubin levels.
Toxic Effect: High levels of bilirubin are toxic to the central nervous system (CNS).
Types of Jaundice:
Hemolytic Jaundice: Conditions like sickle cell anemia or malaria.
Obstructive Jaundice: Caused by bile duct obstruction.
Hepatocellular Jaundice: Results from liver damage due to cirrhosis or hepatitis.
Jaundice in Newborns: Frequently caused by decreased activity of bilirubin glucuronyl transferase, leading to increased unconjugated bilirubin levels.
Creatine
Function: Creatine phosphate acts as a high-energy compound formed in muscles capable of donating a phosphate group to ADP, facilitating ATP production.
Importance: This reaction is critical for maintaining intracellular ATP levels during initial phases of intense muscular contraction.
Clinical Relevance: Creatine kinase levels in plasma are utilized to diagnose myocardial infarction.
Synthesis of Creatine: Creatine is synthesized from glycine, the guanidino group of arginine, and a methyl group derived from activated methionine.
Degradation of Creatine
Cyclization: Creatine and phosphocreatine undergo spontaneous cyclization to yield creatinine, which is excreted through the urine.
Excretion Correlation: The quantity of creatinine excreted in urine correlates with plasma creatine levels, making it useful for estimating total body mass and assessing kidney function.
Synthesis of Histamine
Definition: Histamine is a chemical messenger involved in various cellular responses, including allergy, inflammation, gastric acid secretion, and neurotransmission.
Synthesis: Histamine is synthesized via decarboxylation of histidine.
Release Mechanism: It is secreted by mast cells during allergic reactions, leading to symptoms such as a runny nose or sneezing.
Antihistamines: Drugs used to counteract the effects of histamine.
Serotonin
Synthesis Location: Serotonin is synthesized from tryptophan and can be stored in various sites within the body, including the small intestine, platelets, and central nervous system (CNS).
Physiological Roles: Plays key roles in regulating pain perception, blood pressure, body temperature, and sleep cycles.
Catecholamines
Definition: Biologically active amines such as dopamine, epinephrine, and norepinephrine, collectively referred to as catecholamines.
Functions: Dopamine and norepinephrine act as neurotransmitters, while norepinephrine and epinephrine are produced in the adrenal medulla, exerting effects on the body.
Functions of Catecholamines
Beyond their roles in the nervous system, epinephrine and norepinephrine serve as regulatory hormones influencing carbohydrate and lipid metabolism and modulating blood pressure.
Response Triggers: Release of these amines is triggered by stressors such as fright, exercise, cold exposure, or low glucose levels.
Metabolic Effects: An increase in epinephrine stimulates the breakdown of glucose and triglycerides, increasing heart output, forming part of the “Fight or Flight” response.
Synthesis of Catecholamines
Rate-limiting Step: The enzyme tyrosine hydroxylase catalyzes the conversion of tyrosine to DOPA (3,4-dihydroxyphenylalanine), marking the rate-limiting step in catecholamine biosynthesis.
Oxidative Deamination: Catalyzed by monoamine oxidase (MAO).
O-Methylation: Catalyzed by catechol-O-methyl transferase (COMT).
Melanin
Definition: Melanin is a pigment found in several tissues, including the eyes, hair, and skin.
Melanocytes: In the skin, pigment-forming cells are referred to as melanocytes.
Function: Melanin helps protect cellular components from harmful ultraviolet radiation from sunlight.
Synthesis Pathway: Melanin is synthesized from tyrosine, following the enzymatic action of tyrosinase (T.H) leading to a conversion of Dopa to Melanin.
Conclusion
Comprehensive understanding of nitrogen metabolism, including biosynthesis and degradation of nitrogenous compounds such as heme, bilirubin, creatine, neurotransmitters, and melanin, is crucial for grasping their physiological roles and implications in human health.