Porphyrin and Heme Metabolism

HLS Biochemistry, 2018

Objectives

You should be able to

1. Recognize the precursors of heme synthesis, key

steps of heme synthesis

2. Recognize the regulatory step in heme synthesis

and how it is regulated

3. Know some types of porphyria's and the enzymes

which are involved with these disorders

4. Describe regulation of heme synthesis

5. 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

8

8

Succinyl CoA

Glycine**

HEME SYNTHESIS

** 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 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.