Biochem - Heme Metabolism

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what are the symptoms of porphyria

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stomach pain and fits of madness

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based on the nature of the side chains in heme, three types of rings can be identified...

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URO-porphyrin

COPRO-porphyrin

PROTO-porphyrin

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URO-porphyrin

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each of the pyrrole rings has an acetate (A) and a propionate (P) side chain

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COPRO-porphyrin

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each of the pyrrole rings has a methyl (M) and a proprionate (P) side chain

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PROTO-porphyrin

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two of the pyrrole rings have methyl and proprionate. the other two pyrrole rings have methyl and vinyl (V) side chains

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how many different isomers can u have for each of these 3 types of rings

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URO - 4
COPRO - 4
PROTO - 15

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URO-I and URO-III

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URO-I; starting from the top going clockwise: AP AP AP AP

URO-III; starting from top going clockwise: AP AP AP PA

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COPRO-III

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starting from top going clockwise: MP MP MP PM

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PROTO-IX

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starting from top going clockwise: MV MV MP PM

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what has to be the end product in heme biosynthesis pathway? what are the start products? (2)

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proto-porphyrin XI is the end product

glycine and succinyl-CoA are the start products

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what is the rate limiting step in the heme biosynthesis pathway?

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the condensation of glycine and succinyl-CoA by splitting out CoA via 5-ALA synthase to form 5-ALA (STEP 1) this is the committed step, irreversible, and the rate limiting step and major control point

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step 2 of heme biosynthetic pathway

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2 5-ALA's condense to form the pyrrole ring PORPHOBILINOGEN. catalyzed by ALA Dehydratase. This enzyme is inhibited by Pb.

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step 3 of heme biosynthetic pathway

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4 porphobilinogen condense in the presence of deaminase and then cosynthase to make UROPORPHYRINOGEN III

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step 4 of heme biosynthetic pathway

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the four acetate side chains are decarboxylated to make 4 methyl groups -- COPROPORPHYRINOGEN III

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step 5 of heme biosynthetic pathway

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two of the propionate side chains on the copro are oxidized by an OXIDASE to vinyl groups. THEN the whole molecule is oxidized by another OXIDASE to make PROTOPORPHYRIN IX (end product). It becomes a conjugated double bond system all the way around

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step 6 of heme biosynthetic pathway

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a ferrous ion (Fe++) is put into the middle of the protoporphyrin IX ring. its catalyzed by FERROCHELATASE to make HEME

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If making more heme than using, then what?

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the heme will become HEMIN if not in a hydrophobic environment by removing the protein from the heme molecule

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what does hemin control (2)?

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the first step in the pathway is controlled by hemin. it controls 5-ALA synthase's synthesis of 5-ALA. Hemin will also block the movement of this enzyme into the matrix where it works

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what problems (2) does lead poisoning pose?

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Lead will block two of the enzymes in this pathway, both of which use zinc. The dehydratase will be blocked by lead poisoning by displacing the zinc.
The other enzyme blocked is ferrochelatase.

a person could become anemic now since not making enough hemoglobin. so in urine you would find 5-ALA b/c its increased.
if 5-ALA dehydratase is blocked, then less heme --> then body will try to make heme by making more and more 5-ALA.

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Porphyria - first kind of defect

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genetic defect in the DEAMINASE. Porphobilinogen and 5-ALA build up in the blood and urine--> decrease in the synthesis of heme --> body keeps trying to make heme so the concentrations of the 2 mentioned molecules will go up. The nerves in the GI tract and brain are very susceptible to the above 2 molecules and this is what causes the severe pain in the guy and the neuro (madness) problems

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Porphyria - second kind of defect

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defect in the latter part of the pathway with the COSYNTHASE. Not able to make URO-III so have less heme made. the pathway will keep running and trying to make it so get in accumulation of porphobilinogen, 5-ALA, but especially URO-I b/c if ring isnt closed by enzyme then it'll close up by itself making URO-I, which will then be converted to COPRO-I. These 2 compounds can buildup in skin, light reacts with them there --> itchiness, redness, all b/c of free radical formation once the oxygen in these ring systems react with light. THIS IS ALL BECAUSE LIGHT REACTS WITH THE RING SYSTEMS.

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once protein is split off from heme to make hemin, then what happens in the rest of the breakdown of heme?

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Hemin is converted to Biliverdin by Heme Oxygenase. The ring opens up.

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Then what happens to the Biliverdin?

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The biliverdin is then reduced by Biliverdin Reductase to Bilirubin, which is still an open chain. It is not water soluble but biliverdin is.

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Then what happens to bilirubin?

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It is released into the blood and bound to Albumin in order to be transported to the liver.

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Once in the liver, then what happens to bilirubin?

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Bilirubin is reacted with UDP-glucuronide and this reaction is catalzyed by UDP-glucuronide transferase. The products are Bilirubin Diglucuronide (the CONJUGATED form), which is put into hepatic bile, and 2 UDP.

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What happens to the bile in the GI tract?

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the bilirubin diglucuronide converts back to bilirubin. this will be oxidized to urobilinogen and stercobilinogen. some of the urobilinogen will enter the enterohepatic circulation. some of it will get into systemic circulation and excreted in the urine (yellow in urine).

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Prehepatic Jaundice

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events before the liver gets involved. Breakdown of hemeproteins into bilirubin and heme a lot faster than liver can conjugate -> jaundice
Example: hemolytic anemia – rapid lysing of RBC

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Hepatic Jaundice

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problem with liver itself – is able to conjugate the bilirubin but can’t get into canaliculi OR not conjugating at all
Example; hepatitis, cirrhosis

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Posthepatic Jaundice

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most common form; occurs after leaving the liver, bile stone is the most common cause.
bile stone --> obstructive jaundice, it will block the bile’s pathway in the common bile duct
Bile stone composed of bile pigments, bile salts and cholesterol
When bile backs up, will go back up into liver and bile salts will damage the liver as enzymes released
The backup will consist of conjugated bilirubin which will build up in blood and deposit in the skin and sclera of the eye. Pre-hepatic is with non-conjugated bilirubin.
Sclera of the eye has a lot of elastin which has a great affinity for bilirubin --> eyes become yellow, and skin (does not really causes problems, mostly cosmetic)

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Gilbert Syndrome

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Benign, genetic condition where there is a slight elevation in bilirubin (no major elevations) --> due to a defective UDP-glucuronide transferase or defective intracellular binding proteins

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Crigler Najar: Form 1

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genetic defect in the transferase; 2 forms of this defect:

Form 1: very serious, die within one month of birth, do not have the transferase.

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Crigler Najar: Form 2

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Form 2: do have some activity of the transferase - not nearly as serious- more like Gilbert syndrome

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Pancreatic/Liver Cancer

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bile can be blocked --> jaundice (like posthepatic jaundice

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Increased Bilirubin in Infants

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Most infants born slightly jaundice at full-term birth because the transferase enzyme is only induced at birth, takes ~ 24-48 hours to kick in and then bilirubin can get conjugated.

The more premature infants are, the longer it takes to induce transferase --> risk of severe jaundice (don’t want to have bilirubin levels above 18-20mg/dl)

Our bilirubin levels are 0.1-3mg/dl
In premature infants, the bilirubin will then go to the ganglia and eyes --> cause severe mental damage

Prevent hyperbilirubinemia by putting infant under UV light (puts energy into the folded bilirubin and cause it to unfold --> making it more soluble to excrete rather than accumulate)

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Creatine synthesized from...(3)

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synthesized in the liver from the amino acids glycine, arginine, and methionine (SAM)