Heme Synthesis And Breakdown Flashcards
What is structure of heme?
A porphyrin ring that contains 4 pyrrole rings and one ferrous (Fe2+) (there are four porphyrin rings per hemoglobin)
What are the phases of heme synthesis?
Phase one- generation of ALA from glycine and succinyl CoA in mitochondria
Phase two- generation of Coproporphyrinogen III from ALA in the cytosol
Phase three- generation of heme from Coproporphyrinogen III in the mitochondria
What are the enzymes used in phase one of heme synthesis?
ALA synthase
What are the enzymes used in phase two of heme synthesis?
ALA dehydrogenase, PRB deaminase, uroporphyrinogen III synthase, uroporphyrinogen decarboxylase
What are the enzymes used for phase three in heme synthesis?
Coproporphyrinogen oxidase, protoporphyrinogen oxidase and ferrochelatase
What is the cofactor for ALA synthase and what occurs when the cofactor is not present?
The cofactor is Vitamin B6 and without this there is anemia
What happens when lead is introduced into the body?
Lead will disrupt ALA dehydrogenase and ferrochelatase activity. This will result in the accumulation of ALA and protoporphyrin IX- ALA is a neurotoxin so have neuro sx, anemia since no heme production and weakness because no cytochromes developing
What are the sx of lead poisoning and why?
Neurological sx from build up of ALA
Anemia since no heme production
Weakness since no cytochrome production
What is acute intermittent porphyria?
An acute hepatic porphyria that results in a defect in the PRB deaminase. There will be a build up of ALA and PRB
What is congenital erythropoietic porphyria?
An erythropoietic porphyria that results in a defect in uroporphyrinogen III synthase that results in red fluorescence to the tissues due to a build up of uroporphyrin I.
What is porphyria cutaneous tarda?
An acute hepatic and erythropoietic porphyria that results in a defect in the enzyme uroporphyrinogen decarboxylase. This is the most common porphyria in the US.
What is variegata porphyria?
An acute hepatic porphyria that is the result of a defect in the enzyme protoporphyrinogen oxidase. This is the “celebrity porphyria”.
What is heme degraded into?
Heme will degrade into bilirubin
What is the enzyme that will convert heme to biliverdin?
Heme oxygenase by cutting the bridge between the pyrrole rings- it requires oxygen and will create CO2. Fe2+ is also converted Fe3+
What are the enzymes that convert heme to bilirubin?
Heme oxygenase then biliverdin reductase
What happens when bilirubin is released into the blood?
BR is unconjugated/indirect and insoluble till taken to the liver by albumin
What happens to bilirubin in the liver?
Bilirubin is converted from indirect/unconjugated to direct/conjugated via UDP- glucuronyl transferase. This makes bilirubin diglucuronide
What is an important side reaction in the degradation of heme and why?
the conversion of glucose to UDP-glucose then UDP-glucuronic acid. This molecule is used to help convert indirect bilirubin to direct bilirubin. (Bilirubin to bilirubin diglucuronide)
What happens to the conjugated version of bilirubin?
It is stored in the gall bladder till it is released in bile to be excreted through feces or urine.
What happens to bilirubin once it leaves the gallbladder?
It is released into the stomach then will be converted back to bilirubin. This will be broken down further to urobilinogen by micros. From there is it secreted by the kidneys in the form of urobilin or by the intestines as stercobilin.
What is jaundice?
Also known as hyperbilirubinemia. It is when there is excess bilirubin in the blood stream. There is an imbalance in the production and excretion of bilirubin.
What are the three stages that can cause jaundice?
Pre hepatic, intrahepatic or post hepatic
What are the causes of pre hepatic hyperbilirubinemia?
This occurs before the liver can pick up BR. This leads to excess levels of unconjugated BR levels which result from hemolytic anemia, hemorrhaging, or inability of the liver to pick up BR/conjugate it
What will the findings be in a pre hepatic pt?
elevated levels of unconjugated/indirect BR- normal conjugated BR levels, normal liver enzymes (AST and ALT), normal urobilinogen levels in urine but no direct BR present.
What are the causes of intrahepatic hyperbilirubinemia?
occurs in the liver. Impaired hepatic uptake, conjugation or secretion of conjugated BR. Can occur from general liver dysfunction or disorders of enzymes.
What are the findings in a intra-hepatic pt?
Variable increases in unconjugated and conjugated BR depending on the issue. Will have increased AST and ALT levels. Urobilinogen is normal but there is conjugated BR in urine.
What are the causes of post-hepatic hyperbilirubinemia?
Problems with BR excretion. Can be the result of complications with the gall bladder, tumors in liver or drugs.
What are the findings with post hepatic pt?
Elevated levels of conjugated BR in the blood. Small increases in unconjugated BR levels. Normal AST and ALT levels. Conjugated BR in the urine but no urobilinogen. No stercobilin in the feces.
What is the cause of neonatal jaundice?
Occurs for a few reasons- immature hepatic metabolic pathways, deficiency in UDP-GT enzyme, an increase in fetal hemoglobin
What is phototherapy?
a treatment for jaundice that exposes them to a blue fluorescent light. It causes BR to undergo photoconversion to more soluble isomers.
What is Criggler-Najjar Syndrome?
Deficiency in UDP-GT. There are two types- absence of the gene or mutation of the gene
What happens in Criggler-Najjar syndrome type I?
Complete absence of UDP-GT. Get severe hyperbilirubinemia- babies will have BR accumulation in the brain which will cause encephalopathy and brain damage.
What are some therapies involved in managing type one Criggler-Najjar syndrome?
Blood transfusions, phototherapy, heme oxygenase inhibitors, liver transplants
What happens in Criggler-Najjar syndrome type II?
There is a mutation to UDP-GT but the enzyme is still about 10 percent active. Not as severe hyperbilirubinemia
What is Gilbert syndrome?
Reduced activity in UDP-GT but still about 25 percent active. Relatively common (2-10%). Serum BR is relatively low but will increase with fasting, stress or alcohol.
What is hepatitis?
inflammation of the liver. Leads to liver dysfunction. Can be caused by virus, cirrhosis or cancer. Will lead to elevated conjugated and unconjugated BR
