Heme and Melanin Biochemistry Quiz

Conversion of amino acids to specialized products

• Dietary protein intake is typically 100g/day in the U.S.
• Body protein is approximately 400g/day.
• The synthesis of nonessential amino acids varies.
• Amino acid pool is about 30g/day.
• Body protein is approximately 400g/day (varies).

Porphyrins

• Porphyrins are cyclic compounds that readily bind metal ions (ferrous or ferric).
• They contain four pyrrole rings.
• Porphyrin complexes form with metal ions bound to the nitrogen atom of the pyrrole ring.

Properties of methenyl group

• The methenyl bridge is in the oxidized form (-HC-).
• The methylene bridge is in the reduced form (-CH2-).
• Uroporphyrin is the oxidized form.
• Uroporphyrinogen III is the reduced form.

Porphyrin Structure

• Side chains can vary in structure, attached to each of the four pyrrole rings.
• 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 typically important for humans.
• Porphyrins contain four pyrrole rings (A, B, C, and D) joined through methenyl bridges.
• Type I porphyrins are symmetrically arranged.
• Type III porphyrins have different arrangements (asymmetric).

Example of important human and animal hemeproteins

• Hemoglobin transports oxygen in blood.
• Myoglobin stores oxygen in muscle.
• Cytochrome c is involved in electron transport.
• Cytochrome P450 hydroxylates xenobiotics.
• Catalase degrades hydrogen peroxide.
• Tryptophan pyrrolase oxidizes tryptophan.
• Heme proteins are rapidly synthesized and degraded.

Structure of Heme

• Heme contains ferrous iron (Fe²⁺).
• Protoporphyrin IX contains linked tetrapyrrole rings.
• The side chains are methyl (M), vinyl (V), and propionyl (P).

Where does heme biosynthesis take place?

• Hepatocytes synthesize 15% of heme proteins, particularly cytochrome P450.
• The rate of heme synthesis is variable.
• Erythrocyte-producing cells (bone marrow) are active in hemoglobin synthesis.
• About 85% of heme is found in erythroid tissue.
• Mature red blood cells (RBCs) cannot make heme.
• Heme biosynthesis takes place in the mitochondria and cytosol.

Heme Synthesis Steps

• Steps 1 and 2 involve forming a pyrrole molecule.
• Step 3 involves linking four pyrrole molecules.
• Step 4 involves forming the porphyrin ring.
• Steps 5-7 involve decarboxylation and oxidation.
• Step 8 involves incorporating the iron atom.

First step in heme pathway

• The first step in heme synthesis is a committed step.
• It's a condensation reaction between Glycine and succinyl CoA catalyzed by Aminolevulinic acid synthase (ALAS).
• Coenzyme PLP is required.
• ALAS is a rate-limiting step in heme synthesis.
• Two isoforms exist (ALA-S1 and ALA-S2).
• ALA-S1 is in all tissues; ALA-S2 is in erythroid tissue.

Heme synthesis steps

• Steps 1 involves pyrrole formation.
• Step 2 involves pyrrole formation.
• Step 3 involves linear tetrapyrrole formation.
• Step 4 involves tetrapyrrole ring formation.
• Step 5 involves decarboxylation.
• Step 6 involves decarboxylation/oxidation.
• Step 7 involves oxidation.
• Step 8 involves heme formation.

Porphyria: Vampire Disease

• Porphyrias are rare metabolic diseases.
• They result from a defect in heme biosynthesis, causing porphyrin or precursor accumulation.
• Types include hepatic porphyria (chronic or acute) and erythropoietic porphyria.

Chronic Hepatic Porphyria (PCT)

• This is the most common porphyria.
• Patients exhibit photosensitivity and chronic liver disease.
• Photoactive molecules absorb UV light, causing sunburns.
• Urine turns brown/red as affected products build up in the kidneys.

Acute Hepatic Porphyria (AIP)

• This is a different form of hepatic porphyria.
• Patients produce high levels of affected intermediates, leading to urine turning dark red.
• AIP symptoms can include abdominal pain, neurological issues, and muscle weakness.

Degradation of Heme

• About 80-85% of heme comes from red blood cells.
• The heme degradation process mainly occurs in the macrophage system.
• Hemoglobin breaks down into heme and globin.
• Heme gets broken down into bilirubin and then excreted.
• Bilirubin goes through conjugation and excretion.
• Biliverdin is reduced to bilirubin by biliverdin reductase enzyme.

Degradation of Heme and Bilirubin Metabolism

• Bilirubin is transported to the liver.
• It is bound to albumin and enters hepatocytes.
• It is conjugated with glucuronic acid.
• Conjugated bilirubin (CB) is secreted into bile.
• Unconjugated bilirubin is not secreted into bile.
• Bilirubin is excreted in bile, converted to urobilinogen by bacteria in the intestines, then to urobilin (urine) and stercobilin (feces).

Disorder linked to heme degradation pathway: Jaundice

• Jaundice is a clinical syndrome characterized by yellowing of skin and sclerae.
• Elevated bilirubin levels in the blood (hyperbilirubinemia) cause jaundice.
• Types of jaundice include prehepatic, hepatic, and post hepatic.

Types of Jaundice

• Prehepatic (hemolytic) jaundice: results from increased red blood cell destruction (hemolysis).
• Hepatic jaundice: happens when the liver is damaged, affecting bilirubin processing or excretion.
• Post hepatic (obstructive) jaundice: blockages in the bile ducts prevent bilirubin excretion.

Causes of Hyperbilirubinemia

• Hemolytic anemia
• Hepatitis
• Biliary duct stones

Jaundice in newborns

• Most newborn infants show a rise in unconjugated bilirubin (UCB) in their first week.
• This is because the enzyme ( bilirubin UGT) is not fully developed yet.
• High UCB can cause encephalopathy in severe cases.

Catecholamines and melanin

• Catecholamines (like dopamine, norepinephrine, epinephrine) are water-soluble amines derived from tyrosine.
• Melanin is a pigment synthesized from tyrosine.

Catecholamines

• Biologically active and serve as neurotransmitters and hormones in response to stress or low blood sugar.
• They're released from storage vesicles in the adrenal medulla in response to stress and increase the degradation of glycogen and triacylglycerol.

Melanin

• A pigment found in the skin, eyes, and hair.
• Produced by melanocytes, protects skin cells from sunlight’s harmful effects.
• Albinism is a disorder caused by defects in melanin production (often due to defects in tyrosinase).

Synthesis of Catecholamines

• Hydroxylation is the rate limiting step in catecholamine synthesis.
• Enzymes involve tyrosine hydroxylase, DOPA decarboxylase and dopamine β-hydroxylase.
• The end result is the production of norepinephrine, dopamine and epinephrine.

Degradation of Catecholamines

• Catecholamines are inactivated by enzymes monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).
• Metabolites (like homovanillic acid and vanillylmandelic acid) are excreted in urine.

Histamine Synthesis

• Histamine is a chemical messenger that mediates allergic and inflammatory reactions.
• It's synthesized from histidine by histidine decarboxylase in a reaction requiring PLP.
• It is secreted by mast cells in response to allergic reactions or trauma.

Serotonin Synthesis

• Serotonin (5-hydroxytryptamine) is a neurotransmitter produced predominantly in the gastrointestinal tract.
• Synthesized from tryptophan by a two-step reaction (first hydroxylation, second decarboxylation).
• It plays several important roles in the body, including pain perception, sleep regulation, appetite, body temperature, blood pressure, blood clotting and mood.

Creatine Synthesis

• Creatine synthesis starts in the kidneys.
• Several enzymes are involved, including amidinotransferase, methyltransferase and creatine kinase, which use ATP to create creatine phosphate.

Creatinine

• Creatinine is the breakdown product of creatine phosphate.
• Elevated levels of serum creatinine can be a sign of kidney impairment.

Test your knowledge on the biosynthesis of heme and the role of melanin in the human body. This quiz covers crucial concepts such as enzyme functions, side chain configurations, and the physiological relevance of these compounds. Perfect for students of biochemistry and related fields.