RBC METABOLISM - hemosiderin: Fe+phosphate+hydroxide (inc iron)

- no mitochondria = no krebs!  Anaerobic glycolysis, Hexose monophosphate shunt

- Glucose in RBC 90% anaerobic Molecular regulation
o NADH – methemoglobin reductase, 1glucose = 2 NADH - Iron Regulatory Proteins : control mRNA translation
o ATP and 2,3 DPG (Hb regulator, inc in hypoxia) depend on Rapoport-Luebering Shunt o ↑ Fe – Fe4S4 for aconitase activity

Metabolic Processes o ↓ Fe- FeS4 collapses, apoenzyme inactive bind to IRE

- Iron Responsive Elements
• EMP – main pathway (like cornea, lenses, some parts of retina) uses glucose via GLUT1, 90-95% of energy; 1
o Transferrin receptor – binding IRP ↑ transferin
G = 2ATP, 2Lac, NADPH
o Ferritin – binding IRP ↓ ferritin
• HMP/PPP – 10% of energy, maintains reduced glutathione (antioxidant), protect sulfhydyl groups
Clinical
• Methemoglobin reductase – heme as Fe2+ (reduced), 1G = 2NADH - Hemochromatosis - ↑ Fe uptake, liver cirrhosis, pancreas diabetes, bronze pigmentation
• Luebering Rapaport - 2,3-DPG from 1,3DPG (DPG mutase) or 2-DPG (monoPG mutase) o genetic, abnormal HFE (regulator), no complex with receptor

IRON METABOLISM - IDA - Microcytic, hypochromic RBC

- plasma = transferrin cell = ferritin HEME PORPHYRIN METABOLISM
- 3-4 g 68%Hb 27% ferritin
- Hemoglobin: 750 g, 6-8 g new daily, 14% of dietary AA used. 300 mg of heme synthesized daily
- cytochrome, enzymes
Absorption
- synthezised in marrow and nucleated red cells
- ingested becomes Fe++ or chelated, easily absorbed - 4 pyrrole units form ringed structures = heme, pophyrinogen, porphyrin
- heme Fe+++(red meat) reduced to ++ by ascorbate, citrate etc - broken down: linear tetrapyrrole molecules = bile pigments
- duodenum, upper jejunum reg by feedback
- dec pH favors Fe++, inc pH favors Fe+++ Substrates Products Enzymes Notes
- Fe+++ bind to anion, H2O, peroxides, macromolecules, insoluble SuccinylCoA + Glycine a-amino-b-ketoadipate -> ALA synthase mitochondria, rate-
- Feroxidase I (ceruloplasmin) II (major oxidation) a-aminolevulinate limiting
- Phytates, tannins, lead dec. absorption a-ALA + a-ALA porphobilinogen ALA dehydratase cytosol
- Newborns hard to absorb porphobilinogen hydroxymethylbilane Uroporphyrinogen I synthase
(PBG deaminase)
Transport hydroxymethylbilane Uroporphyrinogen I Non-enzymatic Cannot become heme
- Fe +++ -> transferring = 1-chain, 2 homologous c and n terminal, Uroporphyrinogen III UPG III cosynthase
UPG III Coproporphyrinogen III UPG decarboxylase
- 2 Fe bound (1/9), 1 side (4/9), no Fe (4/9)
Coproporphyrinogen III Protoporphyrinogen IX CPG III oxidase mitochondria
- 1/3 normal saturation, 100ug/100ml blood Total Iron Binding Cap 300ug/100ml
Protoporphyrinogen IX ptotoporphyrin IX PPG III oxidase
- ID TIBC ↑ sat ↓ ptotoporphyrin IX heme ferrochelatase
- Hemochromatosis TIBC low, sat normal
Heme regulation
Uptake
- synthesis in RBC 85%, hepatocytes the rest
- receptor in RBC, liver, placenta (# depends on requirements)
- in liver needed for P450 cytochrome for detox
- able to bind 2 transferrin (4 Fe), maximal at pH 5
- Fe+++ oxidation of heme results in hemin (feedback inhibition to ALA synthase)
- transferrin – transferrin receptors – clathrin coated pits – invaginate – endosomes – ↓ pH – iron release –
- Mature RBC no more synthesis
DMTI transport iron through endosome – transferring, receptors recycled
- Control also on ferrochelatase and PBG deaminase
- RBC: Fe  mitochondria for heme production; non-RBC: iron as ferritin and hemosidderin
- transferin receptor – 2 subunit linked by disulfide bond, hydrophilic tail, hydrophobic center Heme catabolism
- iron depleted state = ↓ apoferritin, replete = ↑ - 2 concerns: porphyrin ring hydrophobic, iron conservation
- hemin -> reduced to heme first
Storage 1. heme -> biliverdin thru heme oxygenase (only CO producing step)
- mostly in liver (reticulocytes, hepatocytes) as ferritin and hemosiderin
2. biliverdin -> bilirubin thru biliverin reductase
- ferritin: 4500 ions per protein molecule, apoferritin+FeOOH + PO4
 3. bilirubin -> bilirubind iglucuronide thru UDP glucoronyl transferase = ↑ solubility
4. intestinal bacteria degrades bilirubin to urobilinogens and urobilins

• Measurement: (1) Direct – water-soluble reaction; (2) Indirect - + OH + reagents to react

Clinical – neurological problems, photosensitivity

• Hyperbilirubinemia – jaundice - ↑ bilirubin
• Bilirubin encephalopathy / kernicterus (neonatal) - ↑ unconjugated (insoluble) bilirubin
• Gilbert syndrome – def UDPG transferase
• Crigler-Najjar syndrome – Type I – no UDPG transferase, Type II - ↓ enzyme
• Dubin-Johnson syndrome - ↓ CBR transporter
• Rotor syndrome – impaired biliary excretion
• Benign familial cholestasis - ↓ ATPase