Nitrogen Metabolism and Porphyrins

Nitrogen Metabolism

• Nitrogen disposal is handled by the urea cycle.
• The breakdown of carbon skeletons from nitrogen-containing substances is also important.
• Examples of N-containing substances include:
  • Porphyrins, including heme
  • Creatine
  • Histamine
  • Serotonin
  • Catecholamines
  • Melanin

Porphyrins

• Porphyrins are cyclic compounds that bind metal ions, typically iron (Fe²⁺ or Fe³⁺).
• Porphyrins are crucial components of numerous proteins.
• Metaloporphyrins, including heme, are essential groups in hemoglobin, myoglobin, cytochromes, catalase, and tryptophan pyrrolase.
• Heme is synthesized and broken down at a rate of 6-7 grams daily.
• The structure of porphyrins involves four pyrrole rings linked by a methylene bridge.
• Different porphyrins have various side chains attached to the pyrrole rings.
• Porphyrin types include I, II, III, and IV, each with distinct side chain distributions.
• Porphyrins are synthesized in the liver, and the first reaction and last three reactions occur in the mitochondria, while others occur in the cytosol.
• Formation of 8-amino levulinate (ALA) is a vital step as this reaction is catalyzed by ALA synthase which is the rate-limiting step in the synthesis of porphyrins.
• ALA synthase is inhibited by heme.
• Two ALA molecules condense to form porphobilinogen via ALA dehydratase enzyme.
• Uroporphyrinogen is formed by the condensation of four porphobilinogens.
• Uroporphyrin III is then converted to heme through decarboxylation.
• Heme's structure involves a ferrous ion coordinated within the porphyrin.

Degradation of Heme

• Red blood cells (RBCs) have a lifespan of 120 days.
• Senescent RBCs are broken down in the spleen and liver by macrophages.
• Heme oxygenase, an enzyme, catalyzes the first step in heme degradation.
• The process results in the release of carbon monoxide (CO), biliverdin, and iron.
• Biliverdin is then reduced to bilirubin.
• Bilirubin is transported bound to albumin in the blood.
• Hepatocytes take up bilirubin and add glucuronic acid to it.
• Bilirubin diglucuronide (conjugated bilirubin) is water-soluble and excreted in bile.
• Bacteria in the intestines convert bilirubin diglucuronide to urobilinogen.
• Urobilinogen is then converted to either urobilin or stercobilin, which are excreted in urine and feces respectively.

Creatine

• Creatine phosphate is a high-energy compound found in muscles.
• It acts as a reservoir, storing energy to replenish ATP during periods of intense muscle contraction.
• The rate of creatine phosphate formation is proportional to ATP requirements and thus is high in muscle tissue.
• Creatine kinase (CK) activity in the blood is used diagnostically in cases of myocardial infarction.
• Creatine is synthesized from glycine, arginine, and methionine, primarily in the kidney, liver, and pancreas.

Degradation of Creatine

• Creatine and phosphocreatine spontaneously cyclize to form creatinine, a waste product.
• Creatinine excretion in urine is directly related to the total body mass.
• Elevated creatinine levels in urine indicate possible kidney dysfunction.

Histamine

• Histamine serves as a chemical messenger mediating various cellular responses, including allergic reactions, inflammation, and controlling gastric acid secretion, and neurotransmitter function in the brain.
• It's produced by decarboxylation of histidine.
• Mast cells release histamine in response to allergies.
• Antihistamines are used to counter histamine's effects.

Serotonin

• Serotonin is synthesized from tryptophan.
• It's stored in various parts of the body, including the small intestine, platelets, and the central nervous system (CNS).
• Serotonin plays multiple physiological roles, influencing pain perception, blood pressure regulation, temperature, and sleep.

Catecholamines

• Dopamine, norepinephrine, and epinephrine are classified as catecholamines.
• Catecholamines function as neurotransmitters within the brain and central nervous system (CNS).
• These compounds are crucial components of the "fight-or-flight" response.
• Norepinephrine and epinephrine are synthesized in the adrenal medulla.
• Catecholamines are inactivated by oxidative deamination (MAO) and O-methylation (COMT).

Melanin

• Melanin is a pigment found in various tissues, such as the skin, eyes, and hair.
• Melanocytes are the skin cells responsible for melanin production.
• Melanin protects tissues from the damaging effects of ultraviolet (UV) light.
• Tyrosine is a precursor molecule in melanin synthesis.

Jaundice

• Jaundice results from high bilirubin levels in the blood.
• It manifests as a yellowing of the skin and sclera (whites of the eyes).
• There are various types of jaundice, including hemolytic jaundice (due to excessive red blood cell destruction), obstructive jaundice (due to bile duct blockage), and hepatocellular jaundice (due to liver damage.
• Jaundice can be observed in newborns due to immaturity of bilirubin glucuronyl transferase, an enzyme critical for bilirubin conjugation.

Explore the complexities of nitrogen metabolism, focusing on the urea cycle and the breakdown of nitrogen-containing substances. Learn about porphyrins and their crucial role in binding metal ions and their significance in various proteins such as hemoglobin and myoglobin.