SYLLABUS 23: Metabolism of Heme Flashcards Preview

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Flashcards in SYLLABUS 23: Metabolism of Heme Deck (44):

function of heme?

cofactor for...

1. oxygen carrier proteins like hemoglobin, myoglobin

2. e- tranfer enzymes like mito cytochromes and cytochrome B5 of microsomes 

3. cytochrome P450 drug toxification enzymes 

4. catalase 

5. prostaglandin synthase 

6. tryptophan dixoygenase 

and other enzymes 


where's heme synthesized

mostly in the livery and erythropoetic tissues like marrow 

however all tissues produce heme


where does heme synthesis occur

both mito and cyto 


structure of heme

ring structure, "protoporphyrin IX"

4 pyrrole rings linked by methene bridges

iron in the middle of the ring 


A image thumb

what is heme synthesized from

succinyl CoA + glycine 

succinyl CoA is from valine, methionine, isoleucine, threonine via methylmalonyl mutase-B12 rxn


how does heme itself control the synthesis pathway

1. it inhibits translation of ALA mRNA, activity of ALA synthase, and transfer of ALAS into the mito 

2. inhibit ferrochetolase


what inhibits ferrochetolase


heme, product inhibitor


2nd step of heme synthesis?

2 moles of ALA leave mito -> Cyto; there, via ALA dehydratase condense to form Porphobilinogen, PBG, a pyrrole ring structure 



what is the first step of heme synthesis, where does it occur

in the mito 

succinyl CoA from the TCA cycle or from Valine, Isoleucine, Leucine, or Threonine is present

succinyl CoA + glycine -> delta aminolevulinate, ALA via delta aminolevulinic synthase, ALA synthase w/ cofactor PLP-B6

H+ + CO2 + CoA are released in this rxn

rate limiting step

HEME end-product inhibits it 



overall heme synthesis pathway?

1. in mito, succinyl CoA + glycine -> ALA via ALA synthase, w/ PLP-B6 cofactor; H+ -> CO2 and CoA released 

2. ALA -> Cyto 

2 moles ALA condense via ALA dehydratase -> 4 PBG

3. 4 PBG via Porphobilogen Deaminase + Uroporphyrinogen Synthase -> Uroporphorinogen III 

4. Uroporphorinogen III -> Coproporphorinogen III via Uroporphyrinogen decarboxylase 

5. Coproporphorinogen III -> Protoporphyrinogen IX via coproporphyrinogen oxidase 

5. Protoporphyrinogen IX -> Mito 

6. In mito, Protoporphyrinogen IX -> Protoporphyrin IX via Protoporphyrinogen oxidase 

7. Protoporphyrin IX -> HEME via Ferrochetolase which inserts Ferrous (2+) iron into protoporphyrin, producing Heme IX


which enzymes of the heme synthesis pathway are sensitive to lead?

1. ALA dehydratase which makes ALA -> PBG 

2. Ferrochetolase which makes Protoporphyrin IX -> Heme 


why is lead poisoning toxic

it inhibits ALA dehydratase and ferrochelatase so inhibits heme synthesis 

this causes ALA accumulation -> destroys RBCs -> anemia 


what is the paint chip issue

old paint had lead as base

children may ingest lead paint chips, and this is toxic


difference between heme made in erythropoetic tissue and heme made in liver?

erythropoetic tissue's heme -> hemoglobin

liver's heme -> cytochromes, esp Cytochrome P450 enzymes 


how is Fe toxic

Fe increases ROS 

We ingest most Fe; if loose in blood may be destructive to RBC and WBC b/c catalyzes O2 Radical formation 


how is Fe stored in tissues

in ferritin, a complex of Fe 3+ and apoferritin 


function of ferritin

powerful antioxidant - it binds Fe, makes Fe stable, doesn't catalyze O2 radical reactions (i.e. Fenton rxn, Haber-Weiss rxn) 



in what state is iron absorbed? 

in what state is it carried through the body? 

absorbed: Ferrous (Fe2+) state

carried: Ferric (3+) state by apotransferrin 


how is iron usually found in body

bound to proteins, b/c free Iron is toxic


what does amount of  ferritin in the blood indicate

amount of iron in storage b/c little ferritin is usually present in the blood, but its amount increases as iron stores increase 

thus ferritin amount in blood is most sensitive indicator of amount of iron in body's stores


what is hemosiderin

a ferritin complexed w/ additional iron that cannot be readily mobilized

it's how excess iron absorbed from the diet is stored


what happens if there's a deficiency in a heme biosynthesis pathway enzyme?

accumulation of the porphyrin substrates 

causes symptoms and diseases called porphyrias 



what are important symptoms caused by porphyrias

skin damage, photosensitivity, neurological probelms, GI tract irritation, nausea


why do the symptoms of porphyrias occur?

b/c porphyrins accumulate in the skin, intestinal t rack, brain 

many have = bonds, and are easily oxidized by singlet O2




treatment for porphyrias?

symptomatic treatment


lifetime of a RBC?

120 days


1/2 life of CYT?

10-20 days


what causes heme breakdown?

hemoglobin or CYTP450 enzymes or other enzymes 


how is heme broken down to bilirubin?

1. heme cleaved by heme oxygenase, a CYP450, to biliverdin

requires O2, NADPH

CO is released

this is mixed funciton oxidase

2. biliverdin is reduced by viliverdin reductase to bilirubin

NADPH is the reductant

3. uncojugated/indirect bilirubin + albumin -> liver 

3. in liver, bilirubin is conjugated to glucuronic acid by UDP-Glucuronoyltransferase 

produces conjugated/direct bilirubin 

4. conjugated bilirubin -> gut, or -> kidney 


how is bilirubin transported from nonhepatic  tissues -> liver

binds to albumin, moves as non-conjugated/indirect bilirubin-albumin complex 

goes to liver conjugated to albumin 

once in liver, undergoes conjugation


what happens to bilirubin once in the liver

conjuating enzymes put a glucose residue as UDP-glucuronate on to the bilirubin; make bilirubin diglucuronide 

that -> direct conjugated bilirubin -> bile, -> feces, -> excreted


biliverdin reductase fxn?

biliverdin -> bilirubin 

uses NADPH 


function of heme degredation?

recycle hemoglobin of RBCs which have reached end of their lifespan 

globin is recycled to amino acids, Fe2+ is recycled, and heme is excreted as bilirubin 


what gives feces its brown color

breakdown product of bilirubin diglucunoride 


what gives urine its yellow color

some urobilinogen, an intestinal intermediate, is reabsorbed into blood and excreted as urobilin into urine 

uroblinogen gives urine the yellow color 


cause of jaundice?

accumulation of bilirubin, -> yellowish coloration, bilirubin toxicity, esp to developing brain 



what metabolically underlies cause of jaundice? 

due to hemolysis and RBC breakdown, so bile ducts get blocked 

decreased conjugation enzyes - usually these develop after the first few days of life; newborns thus are very sensitive to having bilirubin accumulate b/c may not have conjugating enzymes 


how to treat jaundiced newborn?

put them under blue light radiation which reacts w/ these e- and fragments the bilirubin to small fragments 


why are aa considered precursors of heme? 

4 aa become succinyl CoA - Met, Isol, Thre, Val - and Succinyl CoA + glycine is the first step of heme synthesis pathway 


why does lead cause anemia? 

it inhibits the ALA hydratase and Ferrochelatase steps of heme synthesis 

this causes accumulation of ALA 

ALA accumulation is toxic -> destroys RBC -> anemia 

additionally, insufficient heme + RBC -> insufficient oxygen-carrying-capacity in blood


how is heme synthesis regulated 

by Heme itself, which end-product inhibits Ferrochetolase
and ALA Synthase, as well as the translation of ALA mRNA, activity of ALA synthase, and transfer of ALAs into the mito. 


"typical" symptoms associated w/ porphyrias?

skin damaged 


neuro problems 

GI tract irritation 



reaction catalyzed by heme oxygenase?

heme oxygenase is a CYP450 that catabolizes heme to biliverdin through a mixed function oxidase reaction that uses O2 + NADPH + H+ -> NADP+ + Fe3+ + CO 



what is oncjugated bilirbin and what function does conjuation provide? 

Conjugated bilirubin is bilirubin in the liver that has been conjugated to glucuronic acid by UDP-glucuonoyltransferase; this conjugated, direct bilirubin is soluble, and can be excreted to the bile. This is as opposed to unconjugated bilirubin, which is not soluble in water. 

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