Acute hepatic and erythropoietic porphyrias: from ALA synthases 1 and 2 to new molecular bases and treatments

Manceau, Hana; Gouya, Laurent; Puy, Hervé

doi:10.1097/moh.0000000000000330

Cited by 26 publications

(7 citation statements)

References 52 publications

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“…The synthesis of haem begins in the mitochondria with the conjugation of succinyl coenzyme A to the amino acid glycine by aminolevulinic acid synthase (ALAS), leading to the production of the porphyrin precursor ALA [ 2 ]. In erythroid precursors, ALA is produced by ALAS2, an isoform whose expression is positively regulated by iron, whereas in the liver and kidneys, ALA is produced by ALAS1, an isoform under the negative control of haem [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Porphyria and kidney diseases

Pallet

Karras

Thervet

et al. 2018

Clinical Kidney Journal

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The kidneys, after the bone marrow and liver, are third in terms of the amounts of haem synthesized daily. Haem is incorporated into haemoproteins that are critical to renal physiology. In turn, disturbances in haem metabolism interfere with renal physiology and are tightly interrelated with kidney diseases. Acute intermittent porphyria causes kidney injury, whereas medical situations associated with end-stage renal disease, such as porphyrin accumulation, iron overload and hepatitis C, participate in the inhibition of uroporphyrinogen decarboxylase and predispose the individual to porphyria cutanea tarda. Even if some of these interactions have been known for a long time, the clinical situations associated with these interrelations have strikingly evolved over time with the advent of new therapeutic strategies for dialysis therapy and a better understanding of the pathophysiological mechanisms of porphyria-associated kidney disease. Physicians should be aware of these interactions. The aim of this review is to summarize the complex interactions between kidney physiology and pathology in the settings of porphyria and to emphasize their often-underestimated importance.

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Section: Introductionmentioning

confidence: 99%

Porphyria and kidney diseases

Pallet

Karras

Thervet

et al. 2018

Clinical Kidney Journal

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“…There are eight different types of porphyria, each of which arises from mutation(s) in the genes for each of the eight enzymes of the heme biosynthetic pathway 2, 3, 6, 7 . With the exception of porphyria cutanea tarda (PCT), all other seven porphyrias are inherited as autosomal-dominant, autosomal-recessive, or X-linked traits 2, 6, 8, 9 .…”

Section: Introductionmentioning

confidence: 99%

“…to propose that predisposing- or protective-modifier genes alter expression of the AIP phenotype 58 . Indeed, a small number of modifier-genes, regulatory and pathophysiological mechanisms have since been identified to contribute to onset of porphyrias, though these findings remain insufficient to explain the disease-penetrance puzzle 8, 20 .…”

Section: Introductionmentioning

confidence: 99%

Iron Hack - A symposium/hackathon focused on porphyrias, Friedreich’s ataxia, and other rare iron-related diseases

et al. 2019

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Background: Basic and clinical scientific research at the University of South Florida (USF) have intersected to support a multi-faceted approach around a common focus on rare iron-related diseases. We proposed a modified version of the National Center for Biotechnology Information’s (NCBI) Hackathon-model to take full advantage of local expertise in building “Iron Hack”, a rare disease-focused hackathon. As the collaborative, problem-solving nature of hackathons tends to attract participants of highly-diverse backgrounds, organizers facilitated a symposium on rare iron-related diseases, specifically porphyrias and Friedreich’s ataxia, pitched at general audiences. Methods: The hackathon was structured to begin each day with presentations by expert clinicians, genetic counselors, researchers focused on molecular and cellular biology, public health/global health, genetics/genomics, computational biology, bioinformatics, biomolecular science, bioengineering, and computer science, as well as guest speakers from the American Porphyria Foundation (APF) and Friedreich’s Ataxia Research Alliance (FARA) to inform participants as to the human impact of these diseases. Results: As a result of this hackathon, we developed resources that are relevant not only to these specific disease-models, but also to other rare diseases and general bioinformatics problems. Within two and a half days, “Iron Hack” participants successfully built collaborative projects to visualize data, build databases, improve rare disease diagnosis, and study rare-disease inheritance. Conclusions: The purpose of this manuscript is to demonstrate the utility of a hackathon model to generate prototypes of generalizable tools for a given disease and train clinicians and data scientists to interact more effectively.

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“…The main clinical hallmark of XLPP, on the other hand, is protoporphyrin IX production far exceeding the amount of ferrous iron (Fe 2+ ) and the needs for heme synthesis in the bone marrow [ 10 ]. Given this unbalanced ratio of protoporphyrin to Fe 2+ , the heme-synthesizing enzyme, protoporphyrin ferrochelatase, incorporates the alternative metal ion substrate Zn 2+ into protoporphyrin [ 13 ]. Thus, elevated plasma protoporphyrin and Zn 2+ -protoporphyrin levels are observed in XLPP patients [ 10 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…Given this unbalanced ratio of protoporphyrin to Fe 2+ , the heme-synthesizing enzyme, protoporphyrin ferrochelatase, incorporates the alternative metal ion substrate Zn 2+ into protoporphyrin [ 13 ]. Thus, elevated plasma protoporphyrin and Zn 2+ -protoporphyrin levels are observed in XLPP patients [ 10 , 13 ]. All of the identified human ALAS2 mutations associated with XLPP reside in exon 11 encoding the C-terminus of the protein [ 9 , 11 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Anti-Correlation between the Dynamics of the Active Site Loop and C-Terminal Tail in Relation to the Homodimer Asymmetry of the Mouse Erythroid 5-Aminolevulinate Synthase

Catena

Kong

et al. 2018

IJMS

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Biosynthesis of heme represents a complex process that involves multiple stages controlled by different enzymes. The first of these proteins is a pyridoxal 5′-phosphate (PLP)-dependent homodimeric enzyme, 5-aminolevulinate synthase (ALAS), that catalyzes the rate-limiting step in heme biosynthesis, the condensation of glycine with succinyl-CoA. Genetic mutations in human erythroid-specific ALAS (ALAS2) are associated with two inherited blood disorders, X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP). XLSA is caused by diminished ALAS2 activity leading to decreased ALA and heme syntheses and ultimately ineffective erythropoiesis, whereas XLPP results from “gain-of-function” ALAS2 mutations and consequent overproduction of protoporphyrin IX and increase in Zn2+-protoporphyrin levels. All XLPP-linked mutations affect the intrinsically disordered C-terminal tail of ALAS2. Our earlier molecular dynamics (MD) simulation-based analysis showed that the activity of ALAS2 could be regulated by the conformational flexibility of the active site loop whose structural features and dynamics could be changed due to mutations. We also revealed that the dynamic behavior of the two protomers of the ALAS2 dimer differed. However, how the structural dynamics of ALAS2 active site loop and C-terminal tail dynamics are related to each other and contribute to the homodimer asymmetry remained unanswered questions. In this study, we used bioinformatics and computational biology tools to evaluate the role(s) of the C-terminal tail dynamics in the structure and conformational dynamics of the murine ALAS2 homodimer active site loop. To assess the structural correlation between these two regions, we analyzed their structural displacements and determined their degree of correlation. Here, we report that the dynamics of ALAS2 active site loop is anti-correlated with the dynamics of the C-terminal tail and that this anti-correlation can represent a molecular basis for the functional and dynamic asymmetry of the ALAS2 homodimer.

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Acute hepatic and erythropoietic porphyrias: from ALA synthases 1 and 2 to new molecular bases and treatments

Abstract: The knowledge of both the genetic abnormalities and the regulation of heme biosynthesis has increased over the last 5 years and open new avenues in the management of erythropoietic and acute hepatic porphyrias.

Cited by 26 publications

References 52 publications

Porphyria and kidney diseases

Porphyria and kidney diseases

Iron Hack - A symposium/hackathon focused on porphyrias, Friedreich’s ataxia, and other rare iron-related diseases

Anti-Correlation between the Dynamics of the Active Site Loop and C-Terminal Tail in Relation to the Homodimer Asymmetry of the Mouse Erythroid 5-Aminolevulinate Synthase

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