Hemoglobin and Heme (PDF)

RBC shape important to be able to squeeze it + maximize surface area —> important for its function (oxygen and CO2 exchange) Hemoglobin and heme 4 polypeptide chains - 2 alpha and 2 beta deficiency in histidine globin chains = decrease in hematocrit = - 4 x pyrrole N decrease Hb Histidine aa near...

RBC shape important to be able to squeeze it + maximize surface area —> important for its function (oxygen and CO2 exchange) Hemoglobin and heme 4 polypeptide chains - 2 alpha and 2 beta deficiency in histidine globin chains = decrease in hematocrit = - 4 x pyrrole N decrease Hb Histidine aa near central - Histidine (binds Fe) synthesis iron and changes charges —> stabilizes - Oxygen ring and helps it bend — > essential for transport Heme group of oxygen synthesized separately Heme made from glycine, ring structure of 4 pyrrole N with iron in center https://evolutionnews.org/2012/10/gene_duplicatio/ Different forms of hemoglobin        w oxygen bound color: red Oxy-Hb Deoxy-Hb Carboxy-Hb (CO bound) how much CO2 is returned in exhaled in Carbamino-Hb (CO2 bound to globin) lungs NOT BOUND TO HEME NO binds to globin Met-Hb Fetal Hb without oxygen bound color: darker color, burgundy bc less oxygen and more deoxy CO bound more strongly than oxygen is Once CO is bound, Hb won’t let it go —> Oxygen won’t replace it —> very toxic —> make us sleepy and eventually we die Color: cherry red special product of arginine transport to capillaries/to dilate blood vessels oxidized Hb color: brown —> iron oxidized in Hb Met=not methionine Myoglobin: store of oxygen in muscle to enable aerobic metabolism Oximeter: measure Oxy-Hb Must be greater than 95% —> usually 97% oxy If below 90%: respiratory distress Fetal hemoglobin SpO2 At 50% oxygen saturation: lower partial pressure for fetal than adult —> allow it to pick up oxygen from Hb in uterine circulation how much oxygen is available 1/4 of cells in our body: RBC Glucose metabolism in erythrocytes Hyperglycemia: high glucose concentration in RBC 5/6: pathway really important even if only 10% of glucose abt same concentration as in plasma GLUT1 release to tissues 1 hexokinase 3 5 2 ATP levels in cell depends on glycolysis and influence 7 equilibrium in between Hb and HbO2 6 8 2: glycosylation of Hb spontaneously use it as biomarker of hyperglycemia over long terme RBC circulates for 120 days High = poor glycemic control >76.5% = insulin resistance —> normally 5% in healthy ppl —> blood glucose 5 mmol/L so for equilibrium, glucose in RBC (and not 0%) bc we need to regenerate redox capacity of the cell : need to get NADPH and regenerate 3 free GSH (major antioxidant —> protection of the cell) 4 going to liver via Cori cycle to GNG 8: only way to get ATP is through glycolysis (generation of 2 ATP) G6PD deficiency    Glucose-6-phosphate dehydrogenase G6PD generates NADPH, which regenerates GSH Most common genetic disease     shutoff pathway of redox and GSH regulation X-linked recessive, many SNPs 400 million people, 4000 deaths Infection/fava beans cause oxidative stress, AGE’s(advanced glycation endproducts), hemolytic bilirubin: degradation product of heme cause jaundice if bilirubin > than liver anemia, increased bilirubin, jaundice can capacity to detox less susceptible to Heterozygotes are protected against malaria RBC parasite form mosquito Ferritin (Fe+3 ) Iron Metabolism Fe+2 Fe+3 Transferrin heme catabolized into Bilirubin aa ring structure without Bone Marrow porphyrin the iron inserted into it Fe+2 + protoporphyrin Fe Ferritin stores Liver Fe+3 heme Hemoglobin - Hb RBCs Sequential changes with development or iron deficiency Depletion of iron stores 1.  ↓plasma ferritin biomarker of how much iron is bound in the liver Changes in iron transport 2.     ↑absorption efficiency to have more binding site for iron to be up ↑transferrin iron binding capacity picked usually 1/3 are saturated in transferrin ↓transferrin saturation % in bone marrow make more receptors so we can more efficiently picked ↑transferrin receptors would up the Fe2+ + propophyrin more efficiently Defective erythropoiesis 3.   ↓plasma iron Erythrocyte protoporphyrin free protoporphyrin: no iron in heme ring, so can’t function Iron Deficiency Anemia 4.   small pale bc iron in heme that causes red color Microcytic hypochromic erythrocytes lack of energy for neurodevelopment for infant Associated behavioural signs consequences and child Ferritin (Fe+3 ) Iron Metabolism Fe+2 Fe+3 Transferrin Bilirubin Bone Marrow Fe+2 + protoporphyrin Fe Ferritin stores Liver Fe+3 heme Hemoglobin - Hb RBCs Causes of iron deficiency Decreased dietary iron 1.   Less iron absorbed Vegetarian diets lack heme Inhibition of absorption in GI tract 2.   Mineral interactions: Ca, Zn supplements can decrease iron absorption Absorption inhibitors Increased red cell mass 3.  Pregnancy, growth Increased losses 4.    Hemolysis GI bleeding (occult) Heavy menstrual losses Iron deficiency anemia Diagnosis  4 3 Hb < 140 in men, 120 mg/L in women Defective hematopoiesis  2  Decreased transport  1  Free erythrocyte protoporphyrin Decreased transferrin saturation Decreased stores  Decreased ferritin Iron intake and requirement Male Female Iron Balance…RDA Intake minus losses  What intake is required to balance these losses? bc of absorption, RDA higher than the loss  Total: 1.0 mg (males) 1.4 mg (premenopausal females)  GI losses:   RDA:  men: 8 RDA, 1 loss women: 18 mg/day RDA, 1.5 loss     GI blood (Hgb 0.35 mg) GI mucosal (ferritin 0.10 mg) Bile (0.20 mg) Desquamated skin cells and sweat (0.2-0.3 mg) Urinary losses (<0.1 mg) Menstrual losses (0.5 mg) Increases loss by 50% for women compared to men Iron absorption Heme iron    Non-heme elemental iron 25% absorbed Absorbed as heme Fe released in mucosal cell    Absorption highly variable: 1 – 50% absorbed, average <10% Released from ligands by gastric HCl Absorbed as Fe2+ reduced ferrous iron not as Fe3+ oxidized ferric iron reduced form will improve absorption: eating it with orange juice (vit C) will increase absorption 10 – 15% overall Regulation of Iron Absorption (and release from stores) Efficiency of absorption and release is increased in the deficient state Brush border:  increasing synthesis of intestinal reductase, divalent metal that absorbs in Fe2+ transporter DMT1 iron state Basolateral:  increasing synthesis of ferroportin need carrier to transport it to the basolateral side of the cell: ferroportin Hepcidin Regulates iron absorption and release from stores  Hepcidin    Ferroportin   Iron transporter on basolateral membrane of enterocytes and reticuloendothelial cells Iron deficiency   Peptide hormone from liver Decreases ferroportin Decreases hepcidin release which increases ferroportin and efficiency of iron absorption Anemia of chronic disease and infections  IL-6 increases hepcidin, transferrin Hepcidin regulates systemic iron homeostasis Iron overload and toxicity  Hemochromatosis:    Chronic iron overload with tissue damage 5+ types – autosomal recessive Defective regulation of hepcidin synthesis (decreased)      Increased ferroportin synthesis Very efficient iron absorption Iron deposition as hemosiderin -- cirrhosis More common than iron deficiency in men add extra iron in food bc increase risk of iron toxicity Implications for public policy can’t with ppl with hemochromatosis Erythropoiesis Decreased O2 supply Kidney major Liver minor Erythropoietin EPO used to increase oxygen supply: illegal Proerythroblasts in bone marrow Erythroblasts - DNA decreases - Nucleus extruded - Mitochondria disappear 2.4 million synthesized /second early Intermediate late Reticulocytes Blood Mature erythrocytes Increased O2 supply Biosynthesis of Heme - regulated by glucose Acute Intermittent Porphyria • Autosomal dominant • excessive production of ALA and PBG, abdominal pain, neurologic/psychotic episodes • “The Madness of King George” skin manifestation Porphyria Cutanea Tarda • Autosomal dominant • photosensitivity resulting in vesicles and bullae on skin of exposed area; wine red–colored of these products on urine accumulation skin • Living in shade, active at night lead to legend of vampire Source: Heme Fig 16.11 . In: Panini S, ed. Medical Biochemistry: An Essential Textbook. 2nd Edition. New York: Thieme; 2021. doi:10.1055/b000000285 Heme biosynthesis I ALA Synthase Bhagavan, Ha, Essentials of Medical Biochemistry (2nd Ed.), 2015 Heme synthesis & porphyrias γ-Amino-levulinate PBG synthase PBG deaminase Linear tetrapyrrole Uroporphyrinogen III UPG decarboxylase Porphobilinogen Heme Ferrochelase Protoporphyrin IX Coproporphyrinogen III Heme degradation to urobilin and stercobilin in bile Source: Heme Fig 16.13 . In: Panini S, ed. Medical Biochemistry: An Essential Textbook. 2nd Edition. New York: Thieme; 2021. doi:10.1055/b000000285 Hyperbilirubinemia or Jaundice (icterus) itchy in skin high  Pre-hepatic – bilirubin production   Hepatic – bile formation   Increased RBC degradation causing high unconjugated bilirubin, hemolysis, G6PD deficiency, malaria Liver disease, impaired bilirubin conjugation Post-hepatic – bile removal no secretion of bile    bilirubin can’t be removed congenital blockage Cholestasis, biliary atresia, blocked bile duct gallstone ? pale faces bc intermediates are not getting from the bile the GI tract Pale feces, dark urine – why? tourine dark bc bilirubin will be directed to blood and urine Neonatal particularly premature immaturity of enzyme therapy: blue light to breakdown bilirubin accumulated secretion iron heme prot 3 1 5 2 6 7 8 4 Summary of inherited and acquired conditions of RBCs Inherited Acquired G6PD deficiency Sickle cell (prot)   Dietary histidine deficiency (prot) IL-6 inflammation/infections Learning Domains: 1. Biochemical and chemical nature of nutrients 2. Processing of nutrients from the diet 3. Importance of gene function in the processing of nutrients 4. Regulation and dysregulation of nutrient metabolism 5. Inherited and acquired metabolic syndromes 6. Mechanisms by which nutrients regulate gene expression and function 7. Strategies used to study problems in human nutrition and metabolism 8. Integration of metabolism from the cellular to whole body level 9. Nutrition research processes and experiences to inform nutrition knowledge and practice