Biochemistry of Melanin and Serotonin

Conversion of amino acids to specialized products

• Dietary protein intake is typically 100g/day in the US.
• Body protein is approximately 400g/day.
• Amino acid pool synthesis is about 30g/day.
• Synthesis of specialized products from amino acids includes porphyrins, creatine, neurotransmitters, purines, pyrimidines, and other nitrogen-containing compounds.
• Nucleic acid metabolism is involved.
• Glucose, glycogen, ketone bodies, fatty acids, and steroids are produced.

Porphyrins

• Porphyrins are cyclic compounds readily binding ferrous or ferric ions.
• They comprise four pyrrole rings.
• The formation of complexes with metal ions involves nitrogen atoms in the pyrrole ring.

Properties of methenyl group

• A methenyl bridge is an oxidized form.
• A methylene bridge is a reduced form.

Porphyrin Side Chains

• Uroporphyrin I has acetate and propionate side chains.
• Coproporphyrin has methyl and propionate side chains.
• Protoporphyrin IX has methyl, vinyl, and propionate side chains.

Porphyrin Side Chains Distribution

• Only type III porphyrins are important for humans.
• Porphyrin contains four pyrrole rings (A, B, C, and D), joined by methenyl bridges.
• Uroporphyrin I shows symmetrical arrangement of side chains.
• Coproporphyrin and Uroporphyrin III are asymmetrical.

Hemeproteins

• Hemoglobin transports oxygen in the blood.
• Myoglobin stores oxygen in muscle.
• Cytochrome c is part of electron transport chains.
• Cytochrome P450 is involved in the hydroxylation of xenobiotics.
• Catalase degrades hydrogen peroxide.
• Tryptophan pyrrolase oxidizes tryptophan.

Structure of Heme

• Heme contains ferrous iron (Fe2+).
• Protoporphyrin IX contains four pyrrole rings linked by methenyl bridges.
• The side chains are: methyl (M), vinyl (V), and propionyl (P).

Heme Biosynthesis Location

• Hepatocytes synthesize about 15% of heme proteins, particularly cytochrome P450.
• Erythrocyte-producing cells in bone marrow synthesize about 85% of heme.
• The rate of synthesis is variable.
• Heme biosynthesis occurs in mitochondria and cytosol.

Heme Synthesis Steps

• Steps 1 and 2 form a pyrrole molecule: a compound containing four carbon atoms and one nitrogen atom joined in a ring structure.
• Step 3 links four pyrrole molecules to form a linear tetramer.
• Step 4 forms the porphyrin (tetrapyrrole) ring.
• Steps 5-7 involve decarboxylation and oxidation.
• Step 8 incorporates the iron atom.

First Step in Heme Pathway

• Heme pathway's first step is a committed step.
• It involves a condensation reaction between glycine and succinyl CoA.
• The reaction is catalyzed by the mitochondrial enzyme aminolevulinic acid synthase (ALAS).
• ALAS requires coenzyme PLP.
• This is a rate-limiting step.
• Two isoforms of ALAS exist, ALA-S1 located in all tissues, and ALA-S2 in erythroid tissues.

Porphyria (Vampire Disease)

• Porphyrias are rare metabolic diseases that can result in a defect (deficiency) in heme biosynthesis.
• Deficiency results in the accumulation of porphyrins or porphyrin precursors.
• It's classified as hepatic porphyria (chronic or acute) and erythropoietic porphyria.

Chronic Hepatic Porphyria or Porphyria Cutanea Tarda (PCT)

• This is the most common porphyria.
• Patients are photosensitive and often have chronic liver disease.
• The disease causes a buildup of porphyrins in the body, leading to the production and excretion of red-brown urine.
• Porphyria cutanea tarda (PCT) is often linked to alcohol use.

Acute Hepatic Porphyria or Acute Intermittent Porphyria (AIP)

• AIP leads to the buildup of porphobilinogen in the blood and urine.
• This can cause severe abdominal pain, neurological symptoms, and seizures.

Degradation of Heme

• About 80-85% of heme comes from red blood cells.
• Degradation occurs in the reticuloendothelial system of the liver and spleen.
• Heme is broken down into iron, bilirubin, and globin.
• Microsomal heme oxygenase is an enzyme within the macrophage system catalyzing three oxygenations.
  • The first oxygenation opens the porphyrin ring.
  • The second releases iron.
  • The third releases carbon monoxide.
• Biliverdin is reduced to bilirubin by biliverdin reductase.
• Bilirubin is transported to the liver.
• Conjugation with glucuronic acid makes bilirubin water-soluble, allowing excretion in bile.
• Unconjugated bilirubin isn't secreted.

Jaundice

• Jaundice is a clinical syndrome leading to yellowing of skin, nails, and sclerae caused by elevated bilirubin levels.
  • A buildup of bilirubin.
  • Different types of jaundice (prehepatic, hepatic, posthepatic) are associated with various causes.

Types of Jaundice

• Prehepatic (hemolytic) jaundice: excessive red blood cell breakdown causes high unconjugated bilirubin levels.
• Hepatic jaundice: liver damage impairs bilirubin conjugation, leading to increased unconjugated or conjugated bilirubin.
• Posthepatic (obstructive) jaundice: obstruction of bile ducts prevents bilirubin excretion into the gut, leading to increased conjugated bilirubin.

Causes of Hyperbilirubinemia

• Hemolytic anemia, hepatitis, and biliary duct stones.

Jaundice in Newborns

• Most newborn babies show a rise in unconjugated bilirubin levels in the first week due to lower activity of the enzyme bilirubin UGT.
• Elevated unconjugated bilirubin levels can lead to toxic effects and are treated with blue fluorescent light to convert the bilirubin into more polar compounds that are then excreted.

Catecholamines and Melanin

• Tyrosine is a precursor for catecholamines and melanin.
• Phenylalanine is a precursor for melanin.
• Catecholamines are biologically active water-soluble amines derived from tyrosine.
• They serve as neurotransmitters in the central nervous system (CNS) and hormones during stress response.
• Examples are dopamine, norepinephrine, and epinephrine.
• Melanin is a pigment found in skin, hair, and eyes, protecting from sunlight.

Synthesis of Melanin

• It's synthesized from tyrosine by melanocytes in the epidermis.
• Defects in melanin production lead to albinism.

Degradation of Catecholamines

• Catecholamines have a short half-life and are inactivated by enzymes such as MAO and COMT.
• Common breakdown products include dihydroxymandelic acid, metanephrine, normetanephrine, and vanillylmandelic acid.

Histamine Synthesis

• Histamine is a chemical messenger involved in allergic, inflammatory, and gastric acid secretion responses.
• It's synthesized from histidine by histidine decarboxylase, requiring pyridoxal phosphate (PLP).
• Mast cells secrete histamine in response to trauma or allergic reactions.

Serotonin Synthesis

• Serotonin (5-hydroxytryptamine) is produced predominantly in the gastrointestinal tract.
• It's synthesized from tryptophan.
• It's inactivated by MAO.
• It's involved in various physiologic processes.

Creatine Synthesis

• Amidinotransferase is a mitochondrial enzyme essential in creatine synthesis.
• Methyltransferase uses S-adenosylmethionine as a one-carbon donor for creatine synthesis.
• Creatine kinase catalyzes the phosphorylation of creatine, using ATP as a phosphate donor.
• Degradation involves spontaneous cyclization of creatine/creatine phosphate creating creatinine.
• Serum creatinine levels in the blood commonly used to diagnose kidney issues.