Porphyrin and Heme Metabolism

A major metabolic fate of glycine is the biosynthesis of tetrapyrroles, compounds which contain four linked pyrrole rings. Four classes of these compounds include 1) Heme (an iron porphyrin); 2) Chlorophylls; 3) Phycobilins (photosynthetic pigments of algae; and 4) Cobalamins (Vitamin B 12 and derivatives).

All tetrapyrroles are synthesized from -aminolevulinic acid (ALA). Relationships between the various pathways are shown in Figure 21.27.

Heme synthesis:

> 1. All of the nitrogen in heme is derived from glycine and all of the carbons are derived from succinate and glycine. Thus, the process by which heme is synthesized is also called the succinate-glycine pathway. The first step in the process is catalyzed by a pyridoxal phosphate-containing enzyme, -aminolevulinic acid synthetase (ALA synthetase) (Figure 21.28). In plants, ALA is made via a process that begins with glutamate, which becomes linked to a molecule of tRNA (Figure 21.29). In plants, synthesis of ALA is regulated by light.

> 2. The next step is the synthesis of a substituted pyrrole compound, porphobilinogen from ALA (see here).

> 3. The four porphobilinogen molecules condense to yield a porphyrinogen (Figure 21.30).

> 4. Finally, the side chains are modified and the ring system is dehydrogenated (Figure 21.30).

Note that uroporphyrinogen III is an asymmetric compound. It arises from action of uroporphyrinogen I synthase and uroporphyrinogen III cosynthase. If only the first enzyme is active, the symmetric compound, uroporphyrinogen I is produced. In the hereditary condition called congenital erythropoietic porphyria, the uroporphyrinogen III cosynthase is defective and the symmetric type I porphyrins accumulate, causing the urine to turn red, the skin to become photosensitive, and the teeth to become fluorescent. Because insufficient heme is produced, anemia results.

The major regulatory step in heme synthesis is the ALA synthetase reaction. Through feedback inhibition, heme regulates the enzyme. Heme also inhibits the translation of ALA synthetase. At even higher levels, heme blocks transport of ALA synthetase to the mitochondrion - its site of action.

Heme degradation - Erythrocytes have a lifetime of about 120 days. Aged erythrocytes are destroyed upon passage through the spleen or liver (Figure 21.31). The basic pathway of heme breakdown is the following:

Heme -> Biliverdin -> Bilirubin -> (passage through blood to liver as bilirubin-albumin complex) -> Bilirubin Diglucuronide -> excretion.

Bilirubin is insoluble in aqueous solutions, so complexing with albumin and gluruonic acid is essential for passage through the body. Accumulation of bilirubin in the blood leads to jaundice.

See also: Light Absorbing Pigments (from Chapter 17)

INTERNET LINKS:

> 1. Porphyrin and Chlorophyll Metabolism

> 2. Photosynthetic Pigments