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Eric Biochem 3rd Shift Reviewer Rbc Iron Heme

Eric Biochem 3rd Shift Reviewer Rbc Iron Heme

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Published by: api-3742802 on Oct 15, 2008
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03/18/2014

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RBC METABOLISM
-
no mitochondria = no krebs!\ue000 Anaerobic glycolysis, Hexose monophosphate shunt
-
Glucose in RBC 90% anaerobic
o
NADH \u2013 methemoglobin reductase, 1glucose = 2 NADH
o
ATP and 2,3 DPG (Hb regulator, inc in hypoxia) depend on Rapoport-Luebering Shunt
Metabolic Processes
\u2022
EMP \u2013 main pathway (like cornea, lenses, some parts of retina) uses glucose via GLUT1, 90-95% of energy; 1
G = 2ATP, 2Lac, NADPH
\u2022
HMP/PPP \u2013 10% of energy, maintains reduced glutathione (antioxidant), protect sulfhydyl groups
\u2022
Methemoglobin reductase \u2013 heme as Fe2+ (reduced), 1G = 2NADH
\u2022
Luebering Rapaport - 2,3-DPG from 1,3DPG (DPG mutase) or 2-DPG (monoPG mutase)
IRON METABOLISM
-
plasma =transferrin
cell =ferritin
-
3-4 g
68%Hb
27% ferritin
Absorption
-
ingested becomes Fe++ or chelated, easily absorbed
-
heme Fe+++(red meat) reduced to ++ by ascorbate, citrate etc
-
duodenum, upper jejunum reg by feedback
-
dec pH favors Fe++, inc pH favors Fe+++
-
Fe+++ bind to anion, H2O, peroxides, macromolecules, insoluble
-
Feroxidase I (ceruloplasmin) II (major oxidation)
-
Phytates, tannins, lead dec. absorption
-
Newborns hard to absorb
Transport
-
Fe +++ -> transferring = 1-chain, 2 homologous c and n terminal,
-
2 Fe bound (1/9), 1 side (4/9), no Fe (4/9)
-
1/3 normal saturation, 100ug/100ml blood Total Iron Binding Cap 300ug/100ml
-
ID TIBC \u2191 sat \u2193
-
Hemochromatosis TIBC low, sat normal
Uptake
-
receptor in RBC, liver, placenta (# depends on requirements)
-
able to bind 2 transferrin (4 Fe), maximal at pH 5
-
transferrin\u2013 transferrin receptors \u2013 clathrin coated pits \u2013 invaginate \u2013 endosomes \u2013 \u2193 pH \u2013 iron release \u2013
DMTI transport iron through endosome \u2013 transferring, receptors recycled
-
RBC : Fe\ue000 mitochondria for heme production; non-RBC: iron as ferritin and hemosidderin
-
transferin receptor \u2013 2 subunit linked by disulfide bond, hydrophilic tail, hydrophobic center
-
iron depleted state = \u2193 apoferritin, replete= \u2191
Storage
-
mostly in liver (reticulocytes, hepatocytes) as ferritin and hemosiderin
-
ferritin: 4500 ions per protein molecule, apoferritin+FeOOH + PO4
-
hemosiderin: Fe+phosphate+hydroxide (inc iron)
Molecular regulation
-
Iron Regulatory Proteins : control mRNA translation
o
\u2191 Fe \u2013 Fe4S4 for aconitase activity
o
\u2193 Fe- FeS4 collapses, apoenzyme inactive bind to IRE
-
Iron Responsive Elements
o
Transferrin receptor \u2013 binding IRP \u2191 transferin
o
Ferritin \u2013 binding IRP \u2193 ferritin
Clinical
-
Hemochromatosis - \u2191 Fe uptake, liver cirrhosis, pancreas diabetes, bronze pigmentation
o
genetic, abnormal HFE (regulator), no complex with receptor
-
IDA - Microcytic, hypochromic RBCHEME PORPHYRIN METABOLISM

-Hemoglobin: 750 g, 6-8 g new daily, 14% of dietary AA used. 300 mg of heme synthesized daily
- cytochrome, enzymes
- synthezised inmarrow and nucleated red cells
- 4 pyrrole units form ringed structures = heme, pophyrinogen, porphyrin
- broken down: linear tetrapyrrole molecules = bile pigments

Substrates
Products
Enzymes
Notes
SuccinylCoA + Glycine
a-amino-b-ketoadipate ->
a-aminolevulinate
ALA synthase
mitochondria, rate-
limiting
a-ALA + a-ALA
porphobilinogen
ALA dehydratase
cytosol
porphobilinogen
hydroxymethylbilane
Uroporphyrinogen I synthase
(PBG deaminase)
hydroxymethylbilane
Uroporphyrinogen I
Non-enzymatic
Cannot become heme
Uroporphyrinogen III
UPG III cosynthase
UPG III
Coproporphyrinogen III
UPG decarboxylase
Coproporphyrinogen III
Protoporphyrinogen IX
CPG III oxidase
mitochondria
Protoporphyrinogen IX
ptotoporphyrin IX
PPG III oxidase
ptotoporphyrin IX
heme
ferrochelatase
Heme regulation
-
synthesis in RBC 85%, hepatocytes the rest
-
in liver needed for P450 cytochrome for detox
-
Fe+++ oxidation of heme results in hemin (feedback inhibition to ALA synthase)
-
Mature RBC no more synthesis
-
Control also on ferrochelatase and PBG deaminase
Heme catabolism
-
2 concerns: porphyrin ring hydrophobic, iron conservation
-
hemin -> reduced to heme first
1.heme -> biliverdin thru heme oxygenase (only CO producing step)
2.biliverdin -> bilirubin thru biliverin reductase

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