Heme

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primary tissues of heme synthesis

Back 1

1) liver- cytochromes
2) RBC- hemoglobin -HbG

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metabolic starting sources for heme

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1) succinyl coA
2) glycine

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subcellular location

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1) mitochondria
glycine (succinyl coa) to ALA
coproporphrinogen III to heme
2) cytosol
alanine to coprophoryinogen III

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Phases of heme synthesis

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1) synthesis of porphobilinogen
2) formation of the tetrapyrolle ring
3) modification of the tetrapyrolle ring
4) incorporation of iron into the ring

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regulation of heme synthesis

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RDS: delta aminolevulinate synthase

decrease heme activity
1) inhibition
2) repression

requires pyridoxal phosphate

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mechanism of lead poising enzymes involved

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1) delta aminolevuinate synthase
2) aminolevulinate dehydratase
3) ferrocheletase

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mechanism of lead poising basically

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inhibit the enzymes
have VIP-SH groups
Pb chelates these groups
thus inhibiting the enzymes

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what enzyme is the most sensitive to lead poisining and why

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ALA dehydratase

common property of lead poising

increase in ALA dehydratase
without the increase of
porphorybilinogen

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what is heme degredaged into

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biliruin
in the liver

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heme degredagation outline basics

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1) in the liver, bilirubin in conjugated to form BDG which is water soluble
2) in the liver BDG excreted via bile to intestines
3) bile in the intestines
4) bilirubin formed via BDG in the intestines becomes urobilinogens
5) urobilinogens are further metabolized via intestinal bacteria
6) metabolites are eliminated via the feces

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heme oxygenase

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physiological reduction of the CO on the alpha carbon
occurs only in mammilian cells
produces Fe, and CO
product is biliverden

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biliverden reductase

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reduces biliverden via NADPH to NADP to produce bilirubin

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glucose to glucuronate

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2 UDP glucose yeild 2 UDP glucuronate via the oxidation of 2NAD+ --> 2NADH

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bilirubin plus glucuronate

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release of UDP

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porphyrias basics

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rare disorders...defect in heme synthesis
accumulation an excretion of large amounts of porphoryins

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two types of porphryias

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1) erthropoietic (accurs in the RBC)
2) hepatic (occurs in the liver)

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physical manefestation of porphoryias

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acute/chronic skin conditions due to the sensitivity to sunlight

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jaundice basics

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accumulation of bilirubin in blood leads to the yellowing of skin and eyeballs

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three types of juandice

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1) hemolytic
2) obstructive
3) hepatocellular

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hemolytic anemia

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increased destruction of RBC
increased production of bilirubin
increased free bilirubin in plasma

liver becomes overcapacitated to make BDG

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obstructive jaundice

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blocked bile ducts
bilirubin is not delivered to intestines
increased BDG in plasma

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hepatocellular jaundice

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liver damage

decreased ability to make BDG
increased free bilirubin in plasma

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liver damage

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in hepatocellular jaundice

can also include internal bile duct obstruction, free bilirubin and/or BDG may accumulate in plasma

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pre-mature infants and heme deficinies

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liver has not developed the ability to make BDG

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flourescent light

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bilirubin, small less toxic that are eliminated

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porphoryin structure

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ring compounds that bind Fe to the center
precursors for heme in bone marrow and liver

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porphoryin structure

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ring compounds that bind Fe to the center
precursors for heme in bone marrow and liver
Fe2+ is covalently bound to center of the porphyrin ring

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porphoyrin heme is found

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in hemoglobin (RBC)
myoglobin
and cytochromes (liver)

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porphringens basics

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porphryin precursors

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reduced state of porphoryinogens

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colorles and nonflouresncent

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oxidized state of porphoryins

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oxidized to voided urine and exposed to light, become porphoryins,
have a wine-red color under flourecent light

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peripheral circulation porphyrins

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peripheral circulation absorb UV light near skin surface,
becoming photosentizing agents that damage skin and produce vesicles and bullae

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Step 1 heme synthesis

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glycine and succinyl coa are combined with mitochondrial enzyme delta-aminolevulinic acid this forms
dela-aminolevunlinic acid

occurs in the mitochondria

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rate limiting step

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delta aminolevinulic acid
synthetase (ALA synthetase)

requires PLP (vitamin B6)

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suppression of ALA synthatase

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increase in heme
carbohydrate loading (in liver)

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stimulation of ALA synthase

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decrease in heme (after metabolism of a drug) increases activity of enzyme

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Step 2 heme synthesis

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delta aminolevulinic acid is converted into porphobilinogen by the cytosolic enzyme
delta aminolevunilic acid dehydratase (ALA dehydratase)

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regulation of ALA dehydratase

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lead inhibits
leading to increase in delta-aminolevunlic acid

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step 3 heme synthesis

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porphobilinogen is converted into hydroxymethylbilane by the cytosolic enzyme
uroporphyrinogen I synthase

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Acute intermittent porphoryia

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acute intermittent porphoryia

deficiency in uroporphyrigen I synthase

results in the increase in porphobillinogen and ALA in urine

clinical manefestation: neurologic problems

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step 4 heme synthesis

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hydroxymethylbilane is converted into uroporphyrinogen III
by uroporphryinogen III cosynthase

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urophorophoryin I

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hydroxymethylbilane
nonenzymatically converted into uroprophyrinogen I
which is then converted into urophoryin I

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coproporphoyrin I

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hydroxymethylbilane converted into coporphoryinogen I
which is then converted into
corprophoryin I

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congenital erythropoetic porphyria

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deficiency in urophorhyingen III cosynthase

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step 5 heme synthesis

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uroporphyrinogen III is converted into
coprophoryinogen III
by
urophorphyrinogen decarboxylase

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the products of step 5

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can sponteously oxidize into I and I

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step 6 heme synthesis

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corporphoryingon III is converted protophoryingogen IX

protophoryinigen IX --> protophoryin IX via oxidase

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step 7 heme synthesis

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ferrochelatase combines with iron with protophorphryin IX to form heme

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regulation of ALA synthase

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heme feedback regulation
drugs metabolized by cytochrome P450 systen decrease the concentration of heme leading to the activation of ALA synthase

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regulation of ferrochelatase

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lead inhibits ferrocheletase, leading to decrease heme, increase protophoryin IX

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most common reason heme is degraded

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old hemoglobin being degraded via erythrocytes,
phagocytized via macrophages
primarily spleen
once globin is split off

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step 1 in heme degredation

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oxidases convert bilirubin into unbound unconjugated bilirubin in macrophages in the spleen

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what happens to unconjugated bilirubin

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unbound, unconjugated is lipid soluble and is released by the macrophage into the bloodstream

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what is release by the oxidase reaction

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iron and CO

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step 2 heme degredation

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unconjugated bilirubin combines with albumin and is taken up into hepatocytes by binding proteins

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is unconjugated bilirubin filtered in urine

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no, becuase its is lipid-soluble and bound to albumin

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step 3 heme degredation

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in hepatocytes,
unconjugated bilirubin is conjugated by reacting with two molecules of glucoronic acid
UGT (uridine diphosphate glucoronyltransferase)

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what happens to conjugated bilirubin

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actively secreted into bile ducts and stored into gallbladder for eventual relaase into duodenum

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step 4 heme degredation

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intestinal bacteria hydrolyze conjugated bilirubin and reduce free bilirubin to colorless urobilinogen

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urobilin

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oxidation of urobiliogen
gives feces brown color

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step 5 heme degredation

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20% reabsorbed back into the blood in the terminal ileum, recycled back to the liver and kidneys

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urobiligen

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gives urine characteristic yellow color

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bonds within heme

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4 methylations
2 vinyl groups (C=C)
4 pyrrole rings
2 carboxyethyl ch2-ch2-coo-

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amount of substrates needed to synthesize 1 heme

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8 glycine
8 succinyl coa
8 delta-aminolevunlinate (aLA)
1 Uro III
1 Heme

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Phase I

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glycine + succinyl coa via ALA synthetase yeilds ALA
two ALA go to make porphobilinogen

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phase II

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4 porphobilinogen linked together to form uroporphoryinogen III

main enzyme: uropingen I synthase

works with coenzyme uropingen cosynthase III

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what is the purpose of the cosynthase

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last ring undergoes a rotation catalyzed by the uropingen cosynthase III

makes outside groups
APAPAPPA (the last two are switched)

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what are the outside groups

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APAPAPAP

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what does A and B stand for in the heme structure

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A: carboxyl methyl
B: carboxyl ethyl

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phase 3

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Uroporingen III goes to Protopyrin IX
all A groups have been decarboxylated to become methyl groups
two P have changed to become Vinyl groups
this make protoproingen IX
addition of double bonds
make protoporphyrin IX (catalyzed via protophorinigen oxidase)

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phase 4

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ferrocheletase incorporate Fe inside the ring

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outline of heme degredation

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1) heme --> bilirubin outside of liver (intestines)
2) bilirubin has low solubility so the bilirubin is moved to the liver by binding to albumin via albumin complex
3) once inside the liver, bilirubin is conjugated to form BDG (water solubule) than excreted via the bile
4) in the intestine, BDG is reconverted into bilirubin and then converted to urobilinogens---which is excreted via the feces

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how is the heme ring opened

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intact heme ring is opened via heme oxygenase to produce biliverden.
this release the Fe contained inside and carbon monoxid.

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how is carbon monoxide formed

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form the reaction of heme oxygenase opening up the heme ring
alpha carbon

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biliverden

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acted upon by biliverden reductase to form bilirubin
uses NADPH

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how is BDG water solubule

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combining it with 2-UDP glucuronates