Page 264 - Color Atlas Of Pathophysiology (S Silbernagl Et Al, Thieme 2000)

Heme Synthesis, Porphyrias
Heme is synthesized in a chain of eight reac- bile in the stool (coproporphyrins, protopor-
tions (→ A). In addition to its incorporation phyrins), respectively. The porphyrins are pro-
into the hemoglobin of the erythroblasts duced from the respective porphinogens; their
(→ p. 39), heme is synthesized in practically excretory pattern is of diagnostic significance.
all organs and built into myoglobin, cyto- The concentration of δ-ALA is raised by a de-
chrome P 450 , catalase, peroxidase, or the re- ficiency of δ-ALA-dehydratase (= PBG synthe-
spiratory-chain cytochrome. Because these tase) (→ A2) as well as by a hypofunction of
hemoproteins are indispensable, complete ab- porphobilinogen deaminase (also called
sence of heme synthesis is incompatible with hydroxymethylbilane synthetase), the cause
life. Partial, usually heterozygous, defects of of acute intermittent porphyrias (→ A3), in
one of the participating enzymes have severe which the PBG concentration is also increased.
consequences. This results in neurovisceral dysfunctions
Heme synthesis starts with the formation of (tachycardia, nausea, vomiting, constipation)
α-amino-β-ketoadipate that is spontaneously and neuropsychogenic disorders (paralyses, sei-
transformed into δ-aminolevulinate (δ-amino- zures, coma, hallucinations). One of the causes
of these dysfunctions may be the competition
levulinic acid [δ-ALA]). This step, which takes
Metabolism place in the mitochondria, is the rate limiting between δ-ALA and the structurally similar
neurotransmitter γ-aminobutyrate (GABA).
step of heme synthesis; it is catalyzed in the
In
erythroblasts by δ-ALA synthetase 2 (→ A1)
porphyria
congenital
erythropoietic
nonenzymatically from hydroxymethylbilane,
tivity of both isoenzymes is reduced by heme,
8 and in the liver by δ-ALA -synthetase 1. The ac- (→ A4) uroporphyrinogen will be formed
the end-product of the synthesis (negative and converted enzymatically to coproporphy-
feedback; → A, left). This happens in part rinogen I (analogously to A5). Coproporphyrin-
through heme being bound in the cytosol to ogen I can no longer be used metabolically
the heme-regulated element of the proenzyme and, excreted in the urine, in infants it causes
and hindering the latter from passing into the red stains on diapers and later on the teeth.
mitochondria. Other effects are skin reactions to light and he-
Effects of heme synthesis abnormalities dif- molytic anemia.
fer depending on this feedback, depending on In (the more frequent) porphyria cutanea
whether the substrate turnover of δ-ALA-syn- tarda (→ A5) the porphyrins cause damage to
thetase-2 or of one of the subsequent enzyme the skin (poorly healing blisters; → A, photo-
reactions is reduced. In the former case graph) as a result of light absorption (especial-
(→ A1), the heme deficiency can only inade- ly at λ = 440 nm). O 2 radicals are involved in the
quately raise the activity of the deficient δ- generation of the skin lesions.
ALA–synthetase-2, so that a sideroblastic ane- In hereditary coproporphyria (→ A6), as
mia will develop (→ p. 36). also in porphyria variegata (→ A7) (particular-
In deficiencies of the follow-on enzymes ly common in South Africa [ca. three out of
(→ A2–8) a hugely increased availability of δ- every 1000 whites]), δ-ALA, PBG, and the co-
ALA (disinhibition of δ-ALA-synthetase) devel- proporphyrins are all elevated, causing neu-
ops due to the intact negative feedback. As a ropsychogenic and dermatological symptoms
result, the concentrations of the substrates of in the affected children. In protoporphyria (in-
all subsequent reactions are increased and crease of protoporphyrin; → A8) burns, itch-
thus the turnover is increased until enough ing, and pain in the skin due to photosensitiv-
heme has been produced. It is the high concen- ity are prominent after exposure to ultraviolet
trations of the intermediary substances that rays.
lead to abnormalities (primary porphyrias; Acquired porphyrias occur in lead poisoning
→ A2–8). Depending on their solubility in wa- (→ A2,8; high δ-ALA and PBG levels) and in
ter or lipids, the intermediary products are ex- hepatobiliary diseases, in which coproporphy-
254 creted in the urine (δ-ALA, porphobilinogen rin excretion in bile is reduced.
[PBG]), uroporphyrin), or additionally via the
Silbernagl/Lang, Color Atlas of Pathophysiology © 2000 Thieme
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