Porphyrin and Heme Metabolism HLS Biochemistry, 2018

Describe regulation of heme synthesis Objectives You should be able to Recognize the precursors of heme synthesis, key steps of heme synthesis Recognize the regulatory step in heme synthesis and how it is regulated Know some types of porphyria's and the enzymes which are involved with these disorders Describe regulation of heme synthesis Know types and causes of erythropiotic porphyrias

HEME-CONTAINING PROTEINS  Hemoglobin  Myoglobin  Cytochromes  Catalase  Some peroxidases

STRUCTURE OF HEME Ferrous iron (Fe2+) Protoporphyrin IX: contains 4 pyrrole rings linked together by methenyl bridges

HEME SYNTHESIS 8 Succinyl CoA Glycine** Heme ** Amino acid (building blocks of protein) synthesized in your body

Heme synthesis

HEME SYNTHESIS: Red blood cells 85% of total heme synthesis occurs in red blood cells (RBC) Ceases when RBC’s mature Erythroid-specific ALA synthase is regulated by an IRE in the mRNA – binding of IRBP inhibits mRNA translation

HEME SYNTHESIS

In RBCS, heme synthesis is also regulated at the level of the en-zymes ferrochelatase* and porphobilinogen deaminase** * **

HEME SYNTHESIS: Liver The liver is the main non-RBC source of heme synthesis Heme produced in the liver is used mainly for the synthesis of the cytochrome P450 class of enzymes that are involved in detoxification Regulated at level of ALA synthase: Formation of 5-ALA is the rate-limiting step in heme synthesis in the liver

Regulation of ALA Synthase Level of enzyme synthesis Enzyme synthesis, as well as its transport to the mitochondria, is inhibited by elevated levels of heme and hemin, the Fe3+ oxidation product of heme Enzyme synthesis is upregulated by a large number of drugs including barbiturates, steroids with a 4,5 double bond (e.g. testosterone) and some oral contraceptives: These drugs are metabolized by the microsomal cytochrome P450 mono-oxygenase system, a heme- containing protein. Level of enzyme activity Heme and hemin inhibit ALA synthase activity Requires pyridoxal phosphate (Vitamin B6) as a coenzyme

Disorders of Heme Synthesis Acquired: Lead poisoning Congenital: Porphyrias Deficiency of heme has far-reaching effects (hemoglobin, cytochromes, etc.)

LEAD TOXICITY Symptoms Pathophysoiology  Irritability  Poor appetite  Lethargy  Abdominal pain (with or  Sleeplessness without vomiting)  Headaches  Constipation Pathophysoiology  Binds to any compound with a sulfhydryl group  Inhibits multiple enzyme reactions including those involved in heme biosynthesis (PBG synthase & ferrochelatase)  One symptom of lead toxicity is increases in 5-ALA without concomitant increases in PBG

PORPHYRIAS  A group of rare disorders caused by deficiencies of enzymes of the heme biosynthetic pathway The majority of the porphyrias are inherited in a autosomal dominant fashion - thus, affected individuals have 50% normal levels of the enzymes, and can still synthesize some heme Affected individuals have an accumulation of heme precursors (porphyrins), which are toxic at high concentrations Attacks of the disease are triggered by certain drugs, chemicals, and foods, and also by exposure to sun  Treatment involves administration of hemin, which provides negative feedback for the heme biosynthetic pathway, and therefore, prevents accumulation of heme precursors

Scriver et al., The Metabolic & Molecular Basis of Inherited Disease, 8th edition, 2001.