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The d-aminolevulinic acid (pronounce) synthase (ALA synthase) reaction occurs in the mitochondria.
 
d-aminolevulinic acid synthase
(ALA synthase)

The substrates are

  • succinyl CoA (from the tricarboxylic acid cycle)
  • glycine (from the general amino acid pool)

An essential cofactor is pyridoxal phosphate (vitamin B-6)

  • The reaction is sensitive to nutritional deficiency of this vitamin.
  • Drugs which are antagonistic to pyridoxal phosphate will inhibit it. Such drugs include
    • penicillamine
    • isoniazid (isonicotinic acid hydrazide)

The occurs in two steps

  • Condensation of succinyl CoA and glycine to form enzyme-bound a-amino-b-ketoadipate.
  • Decarboxylation of a-amino-b-ketoadipate to form d-aminolevulinate.

This is the rate-limiting reaction of heme synthesis in all tissues, and it is therefore tightly regulated.

There are two major means of regulating the activity of the enzyme.

The first is by regulating the synthesis of the enzyme protein. This is important because its half life is only about one hour.

Enzyme synthesis is repressed by heme and hematin.
 
It is stimulated by
  • barbiturates (as a result, these drugs exacerbate certain porphyrias).
  • steroids with a 4,5 double bond, such as testosterone and certain oral contraceptives. This double bond can be reduced by two different reductases to form either a 5-a or a 5-b product. Only the 5-b product affects synthesis of ALA synthase. Since the 5-b reductase appears at puberty, some porphyrias are not manifested until this age.
 
Summary of regulation of heme synthesis.

The second control is feedback inhibition by heme and hematin, presumably by an allosteric mechanism.

Hence, heme has a dual role in decreasing its own rate of synthesis.

The product of the reaction, ALA, diffuses into the cytoplasm, where the next several steps of heme synthesis occur.

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