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Section 8. Amino Acid Metabolism Porphyrins, heme, bile pigments 11/22/04 Heme • In addition to the heme in hemogloblin and myoglobin, molecules with the porphyrin ring structure include cytochromes, and in plants, the chlorophylls. • Heme is synthesized in most cells. Reticulocytes make ~ 4 x 1012 hemes per second. • In all cases, the precursors are glycine and succinyl CoA. 1 Heme Structure • The core protoporphyrin ring structure is constant. • The sidechains vary in other porphyrins. • The protein structure determines the properties of the prosthetic group. 2 (p270) Protoporphyrin IX Structure O O O O NH N N HN Stryer 4th 3 • Fe(II) displaces the two protons in the center. B12 Coenzyme Structure • Not heme, but similiar. • Compared to a protoporphyrin ring, the corrin ring has smaller space in center to fit Co(II), smaller than Fe(II). • Vitamin B12, cobalamin, may have Co(III) with 5’-deoxyadenosine substituted by CN or CH3. 4 Stryer 4th Succinyl CoA Biosynthesis Valine Methionine CH3 H2C ADP + Pi O propionyl CoA carboxylase propionyl CoA O O H O SCoA Isoleucine - HCO3 + ATP CH3 O SCoA O B12 methylmalonyl CoA mutase methylmalonyl CoA O SCoA succinyl CoA • One heme precursor, succinyl CoA. can be made from propionyl CoA, or from -ketoglutarate in the Krebs cycle. • Propionyl CoA can be made from amino acids, or from the oxidation of odd-numbered fatty acids. • After propionyl CoA is carboxylated, the conversion of methylmalonyl CoA to succinyl CoA requires vitamin B12. 5 Heme Biosynthesis: Part 1 O A CoA + CO2 + O P O O O SCoA succinyl CoA + O + H3N O glycine O O O PLP -ALA synthetase O + NH3 -ALA dehydrase + H 3N NH porphobilinogen -aminolevulinate (-ALA) -ALA synthetase catalyzes the committed + H N 3 step. • Reactions occur in the mitochondrial matrix. • 8 succinyl CoA & 8 glycine. • 6 O porphobilinogen deaminase A P NH P A A NH P NH A P NH a tetrahydropyrrole P A P A A P A P + H3N NH NH NH NH Uroporphyrinogen III Synthetase and Cosynthetase O O O O O Heme Biosynthesis: Part 2 O O O O O O O O + Fe(II) 2 H O O O NH N O NH N N HN O O ferrochelatase N N N N Fe N HN O O O O O uroporphyrinogen III protoporphyrin IX HEME • Notice that one of the pyrrole rings was “rotated” by the uroporphyrinogen cosynthetase making the cyclic uroporphyrinogen III asymmetric (look at the A-P distribution). 7 • The multiple arrows are several decarboxylations. Ferrochelatase Mechanism • Ferrochelatase (FC) binds Fe(II), displacing 2 H+ on the enzyme. • Next it “domes” the protoporphyrin IX. • Fe(II) is inserted, exchanging 2 H+. • It appears that distortion of the protoporphyrin planar structure occurs after the metal binds to FC. • From Blackwood etal, Biochemistry 37:779 (1998). 8 Stoichiometry 8 glycine + 8 succinyl CoA + Fe(II) 1 heme • This ignores the conversion of some of the acetate and propionate groups to methyl and vinyl groups. 9 Control Mechanisms O O • -ALA synthetase catalyzes the CH2 H2C committed step. O • Heme inhibits the activities of H2C -ALA synthetase, -ALA + NH3 dehydrase and ferrochelatase. • Heme also binds a nuclear receptor, which reduces the transcription of the mRNA for ALA synthetase. • Heme inhibits transport of -ALA synthetase into the mitochondria. 10 Diseases Related to Heme Synthesis O O O O O O O O O O O O O O NH N O O O NH N O N HN N HN O O O O O O O O O Asymmetric O O O Symmetric O O • Congenital erythropoietic porphyria is due to deficient uroporphyrinogen III cosynthetase activity in red blood cell precursors. • The symmetric product uroporphyrinogen is not degraded. • Short rbc lifetime, photosensitive skin, red enamel (UV light). • Deficient ferrochelatase causes erythropoietic protoporphyria, 11 which has similar but milder symptoms. Acute Intermittent Porphyria • Due to deficient uroporphyrinogen synthetase activity in the liver, coupled to elevated -ALA synthetase activity. • The result is high [-ALA] and [porphobilinogen]. • Symptoms are abdominal pain, dark urine, neurological aberrations. • King George III ? Vincent Van Gogh ? 12 O O O Heme Degradation O H2O O2 + NADPH N N Fe N N + NADP+ V M M Fe(III) P + CO heme oxygenase O N NH NH O NH biliverdin NADPH biliverdin reductase • Heme is degraded in the liver. • The final product, bilirubin diglucuronide, is transported in O bile from the liver to the gall bladder and excreted. • It, and several related structures, are bile pigments. M • Notice energy is used to reduce biliverdin to a waste product. O V M M 13 V M M P NADP+ P NH NH V M M P NH O NH bilirubin 2 UDP-glucuronate 2 UDP V M NH NH V M M PG PG NH bilirubin diglucuronide NH O Hb Heme Life Cycle • Synthesized in red blood cell precursors. • Spends about 120 days in the bloodstream. • Identified as “old” by the spleen, which disrupts the rbc membrane, freeing the Hb. • Transported to the liver as a haptoglobin-hemoglobin complex. • Degraded in the liver to amino acids, Fe(III) and bilirubin diglucuronide. • The iron is transported to other cells, bound to transferrin, for reuse. • Bilirubin diglucuronide excreted by gall bladder. 14 Bile • About 500 ml per day of bile is made by the liver, which excretes it and transfers it to the gall bladder. • The gall bladder concentrates bile and excretes it into the intestinal lumen. • The three main dissolved constituents are glycocholate (~80%), phospholipids (~15%) and cholesterol (~5%). • Glycocholate, a fat-solubilizing detergent, is reabsorbed by the intestinal epithelium. • The other constituents, such bile pigments, are minor. 15 Gallstone Formation 0 100 Percent Phospholipid Percent Cholesterol 50 50 * 80% bile salt 15% phospholipid 5% cholesterol 0 100 16 * 100 50 0 Percent Bile Salt • At typical total concentrations in bile, the solubility of the constituents is limited (Percent is percent of total solid). • The hatched area includes the combinations of cholesterol, phospholipid and bile salt that are soluble. • Precipitation can lead to gallstones, which are painful if they block the bile duct. Neonatal Jaundice O O O NH O NH O NH NH O bilirubin • The immature liver cannot add glucuronate to bilirubin. • Bilirubin circulates in the blood instead of being transported to the gall bladder. • Bilirubin can cross the immature blood brain barrier and causes brain damage. • Two therapies are successful : – Visible light irradiation. – Sn-substituted protoporphyrin. 17 • Sn-protoporphyrin inhibits heme oxygenase. Next topic: One-carbon metabolism, purine metabolism