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22 Cards in this Set
- Front
- Back
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Biosynthesis of Heme.
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-modular assembly of heme from 8 Succinyl CoA & 8 glycine is partly in mitochondria & part in cytosol
1st step: ALAS (aminolevulinic acid synthase) -use energy from thioester bond to covalently link succinyl coenzyme A to glycine --> CoA + CO2 + delta-Aminolevulinate -occur in mitochondria -uses pyridoxal-5-P cofactor bound by schiff base (double bond N to R group -glycine displaces the lysine side chain then attacks succinyl CoA 2nd step: -aminovulinic acid dehydrogenase (links 2 aminolevulinate together) --> porphobilinogen Third Step: Porphobilinogen Deaminase (tetramer formation) 4th Step: closing the ring Step 5: haircut Final steps 6,7: insert Fe ion |
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Which regulating step is best?
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1st step
-regulated by feedback inhibition -heme product inhibits aminolevulinic acid sythase |
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Porphyrias
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-disease caused by mutations to any heme synthesizing enzyme
-intermediates build up -heme not made (no feedback inhibition) -no regulation of aminolevulinate synthase |
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Porphyrias characteristics
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-colored urine
-skin rashes and blisters -neurological symptoms (peripheral or central) -abdominal pain -accum of intermediates: aminolevulinate, porphobilinogen, porphyrins |
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Why skin rashes and blistering?
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-build up of intermediate
-in skin, exposed parts of body to light activate the poryphrin light absorbtion --> damgae skin |
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Why liver and bone marrow use different ALASs?
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Aminolevulinate synthase 1
-housekeeping, hepatic -high expression in liver -low expression everywhere else -Chromosome 3 -most changes, therefore more highly regulated (heme feedback inhibition)q Aminolevulinate synthase 2 -erythoid specific -highly expressed in bone marrow -should be making consistent heme: no feedback inhibition |
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Structure of Glutamate vs. Aminolevulinate
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X
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Which enzyme mutations wouldn't result in skin rash condition?
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-enzyme 1:aminoleculinic acid synthase
-enzyme 2: prophobilinogen synthase not cyclic compounds, therefore don't absorb light, no color rash result of buildup |
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Porphyria cutanea tarda
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-deficiency of uroporphyrinogen decarboxylase
-most common poryphria -presents w/ skin symptoms only -4th 5th decade of life -brought on by iron overload, sun exposure, hep B or C, HIV infection -urine red/brown -accumulates in urine |
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Heme degradation pathway
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-ring group disrupted --> biliverdin --> bilirubin --> bilirubin digcuronide --> urobilinogen--> Urobilin or stercobilin
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Bruise
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Red: heme group (immediate)
Purple: heme deoxygenated, 1st breakdown, green bile -beyond 2 days -complete conjugated (double bond in middle) Yellowish: bilirubin (red bile) |
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Heme Oxygenase
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-1st regulated state
-not in all tissues -2 isoforms Heme oxygenase 1 -spleen, liver, bone marrow -constitutive -purpsose: catabolism of excess heme antioxidant protection Heme Oxygenase 2 -brain and testis -regulated -Purpose: CO signaling |
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Contrast and Compare Heme and COX 1
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Heme: takes Oxygen and binds and alters the heme
COX 1: binds to heme and modifies the lipid |
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Amount of production and degradation of body heme.
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300mg heme produced
300mg heme degraded -RBCs maintain RBCs mainly degraded in spleen and liver by macrophages -some RBCs processed in bone marrow, lymph by macrophagaes |
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Macrophages phagocytize RBCs and degrade hemoglobin to form:
Heme degraded to form: |
amino acids
bilirubin iron carbon monoxide (good in small amount) |
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Heme Oxygenase
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biliverdin converted to the antioxidant bilirubin
-antioxidant -processed into liver (from mainly spleen and other tissues) transported by albumin |
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What enzymes found in macrophages?
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-biliverdin reductase
-heme oxygenase |
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Process of Degradation of Heme:
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1. RBC broken down by macrophages (spleen, liver)
2. Heme to bilirubin, bilirubin taken up by liver 3. conjugated with glucose to make it more soluble 4. transported/secreted into bile into intestines (rid of it) 5. bacteria in intestines digest to urobilinogen, some oxidized by intestinal bacteria to brown stercoblin 6. rest of urobilinogen is reabsorbed from the gut & enters blood to go to kidney converted to yellow urobilin and excreted |
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Why biliverdin more soluble than bilirubin?
Why not just excrete biliverdin? |
biliverdin, conjugated = planar
bilirubin = elimated double bond -2 independent planar systems -constrained into 2 planes -polar O interacting with H+ from water making it nonpolar, neutralizing charge -want to transform into bilirubin b/c antioxidant -amount of O2 at birth is profound change from umbilical cord -at same time increased bilirubin -bilirubin protecting body's ETC from free radicals |
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Build up of Bilirubin
What would happen without bilirubin? |
Jaundice, start to build up in eyes, skin (yellow color)
-too much = damage brain -kernicturus = toxic levels no antioxidant protection -free radicals take over cell |
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Treatment of Jaundice
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-put under light
-shine light on skin, scrambles cis and trans formation of bilirubin -making compound planar and soluble, decrease build up |
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Why bilirubin insoluble and bilirubin diglucuronide soluble?
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bilirubin O react w/ H2O lowering polarity
conjugated, aded to glucose to O side chains -prevent it from H-bonding with itself, making it soluble in H2O |
