File:Diagnostics-11-02205-g001.png
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[edit]DescriptionDiagnostics-11-02205-g001.png |
English: Figure 1. Mechanisms of neuronal damage in acute hepatic porphyrias. ALAS condenses glycine and succinyl-CoA into ALA, in the first step of the biosynthesis of heme. After an initial series of reactions in the cytosol, coproporphyrin III is imported in mitochondria by ABCB6, a homodimeric porphyrin transporter located in the outer mitochondrial membrane. ALAS is induced by porphyrinogenic stimuli (e.g., fasting, alcohol, or certain drugs) which supposedly induce an increased metabolic demand for heme. In particular, fasting induces ALAS1 expression via the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Lead and succinyl acetone cause a porphyria-like picture since they inhibit ALAD. Acute intermittent porphyria, the most common AHP, is an autosomal dominant disease caused by an abnormal function of HMBS. ALA and (in most cases) PBG accumulate in patients with acute porphyrias during neurovisceral attacks. Givosiran, a siRNA-based drug for the treatment of AHPs, acts by impairing ALAS mRNA translation in the liver. Among other toxic effects, ALA undergoes auto-enolization to yield the highly reactive dioxovaleric acid (DOVA) and other oxidant species; it also interferes with GABA and glutamate receptors. Lack of heme has pleiotropic effects on cytochromes, nitric oxide synthases, tryptophan 2,3-dioxygenase, and several other hemeprotein; it may also affect the regulatory functions of the intracellular “free” heme pool. Pyridoxal phosphate figures among the factors involved in this highly connected network of reactions. Other possible mechanisms of neuronal damage are described in the text. ABCB6, ATP-binding cassette transporter B6; ALA, δ-aminolevulinic acid; ALAD, ALA dehydratase; ALAS, ALA synthase; B6, pyridoxal phosphate; Fe, iron; GABA, γ-aminobutyric acid; HMBS, hydroxymethylbilane synthase; NOS, nitric oxide synthase; Pb, lead. Created with BioRender.com (last accessed date: 22 November 2021). |
Date | |
Source | https://www.mdpi.com/2075-4418/11/12/2205 |
Author | Ricci, A.; Di Pierro, E.; Marcacci, M.; Ventura, P. |
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