Biochemistry of Heme and Porphyrins Quiz

Conversion of Amino Acids to Specialized Products

• Dietary protein intake typical in the U.S. is 100 g/day.
• Body protein is around 400 g/day.
• Synthesis of nonessential amino acids varies.
• Amino acid pool is approximately 30 g/day.
• The body uses amino acids to synthesize various compounds including porphyrins, creatine, neurotransmitters, purines, pyrimidines, and other nitrogen-containing compounds.

Porphyrins

• Cyclic compounds that readily bind metal ions like ferrous or ferric.
• Composed of four pyrrole rings.
• The formation of complexes with metal ions occurs through the nitrogen atom on the pyrrole ring.

Properties of the Methenyl Group

• The methenyl bridge exists in the oxidized form (-HC-) and a reduced form (-CH2-).
• Porphyrin exists in an oxidized or reduced form.

Porphyrin Structure (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 Structure (Side Chain Distribution)

• Only Type III porphyrins are important for humans.
• Porphyrin structure can be symmetrical or asymmetrical.

Hemeproteins

• Hemoglobin is involved in the transport of oxygen in blood.
• Myoglobin stores oxygen in muscles.
• Cytochrome c is part of the electron transport chain.
• Cytochrome P450 is involved in the hydroxylation of xenobiotics.
• Catalase breaks down hydrogen peroxide.
• Tryptophan pyrrolase oxidizes tryptophan.

Structure of Heme

• Heme consists of ferrous iron (Fe2+), protoporphyrin IX and four tetrapyrrole rings linked together by methenyl bridges.
• The side chains include methyl (M), vinyl (V), and propionyl (P).

Heme Biosynthesis Location

• Hepatocytes synthesize 15% of heme proteins, mostly utilizing cytochrome P450.
• Erythrocytes-producing bone marrow synthesizes the remaining 85%.
• Function of the enzymes involves steps in different areas of the cells.

Heme Synthesis Steps

• Steps 1 and 2: Formation of a pyrrole molecule, a compound containing four carbon atoms and one nitrogen atom joined in a ring structure.
• Step 3: Linkage of four pyrrole molecules to form a linear tetramer.
• Step 4: Formation of the porphyrin (tetrapyrrole) ring.
• Steps 5-7: Decarboxylation and oxidation.
• Step 8: Incorporation of the iron atom.

First Step in Heme Pathway

• Condensation reaction between glycine and succinyl CoA catalyzed by aminolevulinic acid synthase (ALAS).
• ALAS is a rate-limiting enzyme in heme synthesis.
• Two isoforms of ALAS exist: ALAS1 and ALAS2. ALAS1 is present in all tissues whereas ALAS2 is produced in erythroid tissue only.

Heme Synthesis Pathway

• A multistep enzymatic process occurs in mitochondria and cytosol.
• Synthesized heme involves various enzymes that are mentioned in the text.

Effect of Alcohol and Drugs on Heme Synthesis

• Alcohol and drugs can affect ALAS1.
• Low heme levels in liver cells increase ALAS1 synthesis.
• CP450 enzymes function in drug detoxification.

Lead Poisoning and Heme Block

• Lead blocks various steps in the heme pathway.
• This can induce various health effects.

Porphyria (Vampire Disease)

• Rare metabolic diseases caused by defects in heme synthesis enzymes.
• Result in accumulation of porphyrin precursors.
• Classified as hepatic porphyria (chronic or acute) or erythropoietic porphyria.

Chronic Hepatic Porphyria (PCT)

• Chronic liver disease.
• Most common porphyria.
• Patients are photosensitive.
• Symptoms include photoactive molecules that absorb UV light, causing sunburns.
• Urine turns red/brown due to built up porphyrins

Acute Hepatic Porphyria (AIP)

• Includes symptoms of urine discoloration.
• Accumulation of porphyrins.

Degradation of Heme

• About 80-85% of heme comes from red blood cells.
• Hemoglobin is broken down to heme and globin which is degraded into amino acids, and then heme to bilirubin.
• This process occurs in reticuloendothelial system cells, mostly in liver and spleen.

Degradation Stages

• Microsomal heme oxygenase catalyzes the three oxygenation steps that result in the formation of biliverdin.
• Biliverdin is reduced to bilirubin by biliverdin reductase enzyme.
• Bilirubin is transported in the blood.
• Bilirubin is taken up by the liver.
• Bilirubin is conjugated with glucuronic acid which makes it more soluble.
• Conjugated bilirubin is secreted into the bile.
• Bacteria in the intestines convert bilirubin to urobilinogen.
• Urobilinogen either gets excreted to urine or into blood.
• Stercobilin leads to the feces.

Jaundice

• Jaundice is a disorder related to elevated bilirubin levels.
• Jaundice can be prehepatic, hepatic, or posthepatic.
• The color of the patient's skin, nails, and sclerae is yellow.

Jaundice in Newborns

• Infants experience increased unconjugated bilirubin levels during the first week primarily due to immature UDPGT in the liver.
• The elevated bilirubin is treated with blue fluorescent light.

Catecholamines and Melanin

• Catecholamines are water-soluble amines derived from tyrosine and are synthesized in the brain as neurotransmitters or in response to stress.
• Melanin is a pigment synthesized from tyrosine in melanocytes, that protects cells from sunlight.
• Albism is a disorder due to a defect in melanin production.

Histamine Synthesis

• Histamine is a chemical messenger in cells involved in allergic reactions and gastric acid secretion.
• Synthesized from histidine by histidine decarboxylase (requiring PLP).

Serotonin Synthesis

• Serotonin (5-hydroxytryptamine) is synthesized from tryptophan predominantly in the gastrointestinal tract.
• It's inactivated by Monoamine oxidase (MAO).
• Serotonin has multiple physiological roles.

Creatine Synthesis

• Creatine is synthesized from the amino acids, glycine, arginine and methionine.
• The rate-limiting step is catalyzed by amidinotransferases.
• Creatine kinase catalyzes the phosphorylation of creatine using ATP, forming creatine phosphate.
• Creatinine is a degradation product that is excreted in the urine.