Synthesis Of Heme Flashcards
Porphyrins
. Cyclic compounds
. Bind to metal ions (ferrous or ferric ions)
. Formed by linkage of 4 pyrrole rings through methenyl bridges
. Pigmented
Ferrous
Fe2+
Ferric
Fe3+
How many types of porphyrins are there and what ones are important to humans?
4 types, type III important because it contains asymmetric substitution of ring D
. Type I may be synthesized in disease process
Porphyringogens
. Porphyrin precursor
. Colorless
. Intermediates heme biosynthesis
. Exists in chemically reduced forms
Heme
. Final product of porphyrin synthetic pathway
What protoporphyrin is important to humans and why?
Type IV because one Fe2+ in center is what heme is
Heme biosynthesis sites
Liver and erythrocyte- producing cells of bone marrow
Where do reaction steps of heme biosynthesis occur?
. Initial and last steps of porphyrin formation are in mitochondria
. Intermediate steps in cytosol
Hemin
. End product inhibitor
. Inhibits formation of aminolevulinic acid (ALA) by decreasing ALA synthase enzyme synthesis
.Overall heme synthesis inhibited because not enough ALA synthase to make ALA for synthesis
. Result of oxidation of Fe2+ to Fe3+ when excess heme accumulates
Drugs that increase ALA synthase activity
Drugs that affect Heme-containing microsomes cytochrome P-450 mono-oxygenase system (barbiturates, sedatives, estrogens)
How do drugs using microsomal cytochrome P450 mono-oxygenase system increase ALA synthase activity?
. Through de-repression
. Major pathway for hydroxylation and detoxification of aromatic/aliphatic compounds
. Drugs need to be metabolized via this pathway so more cytochrome P450 is needed and contains heme
. P450 synthesis inc., more heme consumed in lever, less free heme available, inc. ALA synthase activity and dec. hemin
What does lead inhibit and how?
. Formation of porphobilinogen and formation of heme
. Inhibits ALA dehydratase elevating ALA and anemia
. Inhibits ferrochelatase
ALA dehydratase
Enzyme that catalyze formation of porphobilinogen
. Inhibited by lead
Ferrochelatase
Enzyme that enhances the incorporation of Fe2+ into protoporphyrin IX
Porphyria
. Autosomal dominant (exp. congenital one that’s recessive) Disorders of specific enzymes in heme biosynthesis
. Often autosomal dominant disorders
. Nonspecific
. Decreased heme synthesis
. Increased ALA synthase and heme intermediate production prior to the mutated enzyme
How are porphyria classified?
Hepatic or erythopoietic depending on whether enzyme deficiency occurs in RBC precursors in bone marrow or liver
ALA and porphobilinogen accumulation symptoms
Abdominal pain and neuropsychiatric disturbances
Acute intermittent porphyria has these
Photosensitivty cause
. Enzyme defects that lead to accumulation of tetrapyrrole intermediates
. Porphyrin-mediated formation of superoxide radicals (ROS) from oxygen
. ROS damages membranes and releases lysosomes
Photosensitivity symptoms
. Skin itches and burns when exposed to visible light
Porphyria treatments
. IV hemin injection (inhibits ALA synthase eventually dec. intermediates that built up)
. Avoidance of sunlight
. Ingestion of beta-carotene (free radical scavenger) help when experiencing photosensitivity
Porphyrin accumulation cutaneous symptoms
. Skin or urine that is red to brown in natural light but pink to red in fluorescent light
Lead poisoning
. Elevated ALA in urine
. Can cause anemia is lead level >40 mg/dL
. Affect IO, attention span, and academic achievement in kids that can’t be corrected
. Inc. protopoyphyrin IX in blood bc Fe 2+ can’t be put on to form full heme
Lead level cutoff for ages 1-5
5 micrograms/dL
Signs and symptoms of lead poisoning
. Stomach aches, cramping, constipation and diarrhea
. Nausea. Vomiting
. Persistent unexplained fatigue
. Headache
. Muscle weakness
. Long-lasting effects, coma, and death is leve >80 mcg/dL
T/F patients w/ chronic low levels of lead exposure have no obvious symptoms
T
What therapy is used in attempt to remove lead?
Chelation therapy
Porphyria cutanea tarda
. Chronic, uroporphyrinogen decarboxylase deficiency (UROD)
. Uroporphyrin accumulates in urine
. Most common, usually acquired
. Those w/ UROD genetic deficiency (familial PCT) won’t have symptoms unless large amts porphyrins build in liver then disease becomes active
. Photosensitive
. Onset: 4-5th decade of life
Acute intermittent porphyria
. Acute, porphobilinogen deaminase deficiency
. Porphobilinogen and ALA accumulates in urine
. Urine darkens on exposure to light or air
. NOT photosensitive
. 2nd most common, autosomal dominant, 5-10 of every 10,000 have it
Rate limiting step in heme synthesis
. Glycine + succinyl CoA form ALA via ALA synthase
ALA
Gamma aminolevulinic acid
Heme pathway
- Gly + succinyl CoA -> ALA via ALA synthase
- ALA x2 -> porphobilinogen via dehydration rxn
- Porphobilinogen x4 -> uroporphyrinogen III via condensing rxn
- Uroporphyrinogen II -> protoporphyrin IX
- Fe 2+ introduced to make heme via ferrochelatase
How to test for porphyria
. Quantifying different metabolites
. Screening at genetic level
Porphyria symptoms
. Abdominal pain, neuropsychiatric disturbances (anxiety to delirium)
. Photosensitivity
Porphyria cutanea tarda clinical expression influenced by __
. Fe . Sunlight . alcohol . Estrogen . Hep B/C, HIV . Smoking
What can predispose people to PCT
Hemochromatosis (Fe overload disorder)
PCT symptoms
. Chronic recurring blisters on sun exposed areas
. Skin sensitive to minor injury
. Hair growt on face and other sun exposed areas increases
. Mild liver function abnormalities
. Cirrhosis or liver cancer may develop
Acquired PCT treatments
. Avoiding alcohol
. Phlebotomy
Acute hepatic porphyrias
. ALA dehydratase deficiency porphyria . Acute intermittent porphyria . Hereditary coproporphyria . Variegate porphyria . GI symptoms, neuropsychiatric, motor, photosensitivity
AIP treatment
. Medical support
. Glucose
. Injection of hemin to dec. ALA synthase synthesis
. Avoid barbiturates, alcohol
Erthyropoietic porphyrias
. Congenital erythropoietic porphyria
. Causes skin rashes and blisters
. May be at risk for hepatobiliary disease
