Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

II. Porphyrins
245
TABLE 8-2 Nomenclature for Enzymes of Porphyrin
and Heme Synthesis and Their Synonyms
Abbreviations
Nomenclature
1. ALA-Syn delta-aminolevulinate synthase
(synthetase)
2. ALA-D delta-aminolevulinate dehydrase
(dehydratase); porphobilinogen
synthase
3. PBG-D porphobilinogen deaminase,
uroporphyrinogen I synthase
(synthetase), hydroxymethylbilane
synthase
4. UROgenIII-Cosyn uroporphyrinogen III cosynthase
(cosynthetase)
5. UROgen-D uroporphyrinogen decarboxylase
6. COPROgenIII-Ox coproporphyrinogen III oxidase
7. PROTOgen-Ox protoporphyrinogen oxidase
8. FER-Ch ferrochelatase; heme synthase
(synthetase)
3 . Uroporphyrinogen
Next, two enzymes, porphobilinogen deaminase (PBG-D)
(formerly called uroporphyrinogen I synthase [UROgenI-
Syn]) and uroporphyrinogen III cosynthase (UROgenIII-
Cosyn) act together to condense four moles of PBG into
the cyclic tetrapyrrole, uroporphyrinogen III (UROgenIII).
PBG-D initially catalyzes the formation of a symmetrical
linear tetrapyrrole. UROgenIII-Cosyn then flips the
D ring and closes the pyrroles into an asymmetrical porphyrin
ring of the type III configuration. In the absence
of the UROgenIII-Cosyn, the symmetrical linear tetrapyrrole
spontaneously closes into a symmetrical porphyrin
ring of the type I configuration. Normally, there is a great
excess of UROgenIII-Cosyn, so UROgenIII is synthesized.
Both enzymes have been isolated from the spleens of anemic
mice and in vitro , in the presence of both enzymes,
UROgenIII was produced ( Levin and Coleman, 1967 ).
4 . Coproporphyrinogen
The eight carboxyl UROgens I or III are next progressively
decarboxylated into the four carboxyl coproporphyrinogens
(COPROgen) I or III with the decarboxylations catalyzed by
the enzyme uroporphyrinogen decarboxylase (UROgen-D).
UROgen-D is nonspecific so it catalyzes the decarboxylation
of either UROgenI or UROgenIII. The COPROgens
now move back into the mitochondria ( Fig. 8-4 ).
FIGURE 8-5 Alternate pathways for porphyrin synthesis. Normally,
enzymes 3 and 4 function together in a coordinated manner to form heme.
In the absence of enzyme 4, the alternate and terminal pathway to form
the I isomers is taken. The circled numbers correspond to the enzymes
listed in Table 8-2.
5 . Protoporphyrinogen
Within the mitochondria, coproporphyrinogen III oxidase
(COPROgenIII-Ox) catalyzes the decarboxylation of the
two propionic acid groups on the A and B pyrrole rings of
COPROgenIII to vinyl groups and the resulting product is
protoporphyrinogen III (PROTOgenIII). COPROgenIII-Ox
is highly specific for COPROgenIII, and this explains the
presence of only type III porphyrin isomers in nature. This
also means that COPROgenI is a terminal intermediate that
is oxidized to coproporphyrin I, the end product of this path
( Fig. 8-5 ). COPROgenIII, when in excess, is also oxidized
to coproporphyrin III. Similarly, the UROgens I and III
can be oxidized to their end products, the uroporphyrins I
and III. Figure 8-5 illustrates that each of the -gen forms
can be oxidized into their free forms, which are the forms
usually found in the circulatory system. These free porphyrins
and protoporphyrins are photoreactive and are the
causative agents of the photosensitivity in the porphyrias.
6 . Protoporphyrin
PROTOgenIII, the 2-carboxyl porphyrinogen, is next oxidized
at the carbon bridges to form the methene bridges
connecting the pyrroles and is catalyzed by protoporphyrinogen
III oxidase (PROTOgenIII-Ox). The resulting
product is protoporphyrin IX (PROTO IX).