Molecular Mechanisms of Training Effects
Atko Viru in Adaptation in Sports Training, 2017
It has been suggested that the key role in the increased activity of mitochondrial enzymes belongs to the induction of δ-aminolevulinic acid synthase by exercise.145 The effect of thyroxine is analogous. The activity of this enzyme in the red portion of the vastus lateralis muscle was doubled 17 h after a 4000-m run in rats. A similar change was obtained 14 h after injections of thyroxine. Before that, no change in heme-containing cytochrome c concentration occurred.148 δ-Aminolevulinic acid synthase is a rate-limiting enzyme in heme synthesis. This observation thus implies that up-regulation of heme synthesis is an early regulatory event mediated by muscle contraction and leading to an improvement of respiratory capacity.18
Consequences of an incomplete differential diagnosis
James W. Albers, Stanley Berent in Neurobehavioral Toxicology: Neurological and Neuropsychological Perspectives, 2005
Attacks of porphyria may be precipitated by many factors, the most important being medications (Meyer et al., 1972). The association of drug-induced porphyria has been known for a long time. The strongest precipitators are the barbiturates, although many other medications are implicated. Any drug metabolized by the hepatic cytochrome P-450 system is at risk for precipitating attacks. The barbiturates are known to amplify cytochrome P-450 synthesis as much as 40–50 times (Bissell, 1985; Sack, 1990). When the cytochrome P-450 system is activated, the intracellular heme reserve is incorporated into these hepatic cytochromes. As the heme concentration decreases, aminolevulinic acid synthase is disinhibited, and the porphyrin metabolic pathway is activated. Among patients with porphyria, the pathway is partially blocked, producing accumulation of porphyrin precursors and inhibition of heme synthesis necessary to replace the depleted stores.
Porphyric Red Cells
Ronald L. Nagel in Genetically Abnormal Red Cells, 2019
The first enzyme in the synthesis of heme is b-aminolevulinic acid synthase (ALA-synthase). This enzyme is thought to be the rate-limiting step in the synthesis of heme, at least in the liver,12 and it can be induced by a variety of drugs.13 The activity of ALA-synthase can be regulated by the concentration of heme. Because the half-life of ALA-synthase is only about 70 to 180 min,14,15 this regulation does not seem to occur by direct inhibition of the enzyme. Most probably, heme interferes with the synthesis of ALA-synthase or by shortening the lifetime of the mRNA of the enzyme.15,16 It is also possible that heme can interfere with the transport of ALA-synthase from cytosol to the mitochondria.17,18 ALA-synthase condenses one molecule of glycine with one molecule of succinyl-CoA to form ALA. It is possible that ALA also can be synthesized by another mechanism catalyzed by the enzyme 7-8-dioxovalerate transaminase, which catalyzes the reaction between 7-8-diox-ovalerate (a derivative of glutamate or a-ketoglutarate) and L-alanine.19,20 The importance of this pathway in the synthesis of ALA in humans remains to be elucidated. ALA-synthase activity is increased in most forms of porphyrias, probably due to loss of inhibition by the end product heme. It has been suggested that increased activity of ALA-synthase together with decreased activity of porfobilinogen deaminase should be the best marker to identify patients with acute intermittent porphyria.21
A deep dive into future therapies for microcytic anemias and clinical considerations
Published in Expert Review of Hematology, 2023
François Rodrigues, Tereza Coman, Guillemette Fouquet, Francine Côté, Geneviève Courtois, Thiago Trovati Maciel, Olivier Hermine
Heme synthesis requires three substrates: succinyl-CoA, iron, and glycine. For each heme molecule synthesized, one atom of iron and eight molecules of glycine are needed [65]. It has been shown that reduced delivery of iron to erythroblasts reduces the synthesis of heme. Indeed, as written earlier, the mRNA of aminolevulinic acid synthase 2 (ALAS2), the first-step enzyme of heme production in red blood cells, is regulated by IRPs. In iron-deficiency, IRPs associate with the 5’ UTR IRE region of ALAS2 mRNA to inhibit its translation [15]. Reduced intracellular heme content then activates the heme regulated eIF2alpha kinase (HRI), which represses the translation of globin by phosphorylating the translation initiation factor eIF2 alpha [66]. Decreased heme and globin production thus leads to hypochromic and microcytic anemia in iron deficiency states. Interestingly, the development of microcytic anemia seems necessary for the survival of red blood cells during iron deficiency, as in iron depleted HRI(-/-) mice, globins devoid of heme aggregate within the erythroid lineage, resulting in a hyperchromic, normocytic anemia with decreased RBC counts, compensatory erythroid hyperplasia and accelerated apoptosis in the bone marrow and spleen [67].
Expression profile analysis reveals hub genes that are associated with immune system dysregulation in primary myelofibrosis
Published in Hematology, 2021
Haotian Ma, Jincen Liu, Zilong Li, Huaye Xiong, Yulei Zhang, Yanping Song, Jianghua Lai
5-Aminolevulinic acid synthase (ALAS) is encoded by ALAS2 and can catalyze the formation of 5-aminolevulinic acid from succinyl-coenzyme A and glycine, which is the first step in haemoglobin synthesis [50]. Increased haemoglobin synthesis could promote haematopoietic cell differentiation [51]. The upregulated expression of ALAS2 could cause enhanced haem production, haemoglobinization, and erythropoiesis [52]. In this study, we found that the expression of ALAS2 was enhanced in patients, reflecting that ALAS2, similar to EPB42 and SLC4A1, could affect the abnormally increased erythropoiesis in PMF [53], which may be related to ineffective erythropoiesis. Ineffective erythropoiesis is one of the main causes of anaemia and organomegaly. In addition, several studies revealed that haem- or haemoglobin-related genes were also expressed in non-erythrocyte cells, such as cervicovaginal epithelial cells and murine macrophages, in response to different stress conditions [54,55]. It is well established that haem is an important molecular factor for cellular physiological and metabolic functions. However, excessive free haem has toxic effects on cells [56]. In this study, we conjecture that the enhanced expression of ALAS2 reflects an increased level of haem, indicating a feasible reason for the immunological response in patients with PMF.
Neurological and neuropsychiatric manifestations of porphyria
Published in International Journal of Neuroscience, 2019
Yiji Suh, Jason Gandhi, Omar Seyam, Wendy Jiang, Gunjan Joshi, Noel L. Smith, Sardar Ali Khan
8 Glycine and 8 succinyl-Coa is used by δ-aminolevulinic acid synthase (ALAS) to make ALA within the mitochondria. ALAS-1 expression is activated by PGC-1α within hepatocytes. PGC-1α normally plays a role in liver energy homeostasis. However, PGC-1α is also an important factor that controls that expression of ALAS-1 [8]. PGC-1α may also be activated by the liver in vivo. ALAS enzymatic action is limiting step in heme production due to its feedback inhibition [1]. The ALA is shuttled into the cytoplasm, and becomes porphobilinogen (PBG) with the use of δ- aminolevulinate dehydratase (ALAD). PBG becomes hydroxymethylbilane (HMB) catalyzed by porphobilinogen deaminase (PBG-D). Then, HMB becomes (uroporphyrinogen III) Uro-P with Uroporphrinogen III cosynthase, and coproporphyrinogen (Copro-P) is made with Uroporphyrinogen decarboxylase. Copro-P is then shuttled into the mitcohondria to become proptoporphyrinogen IX by combining with coproporphyrinogen oxidase (CPO). Proto-P is oxidized by protoporphyrinogen oxidase to become protoporphyrin. Protoporphyrin becomes heme by addition of Fe2+ and ferrochelatase [1, 8]. Heme may be produced within the liver or bone marrow. The difference lies in the regulation, as heme regulates the production of heme by inhibiting ALAS which causes the synthesis of heme to slow. The bone marrow, however, contains erythropoietin which controls the formation of heme. Any disorder within these steps except for ALA synthase can cause toxic precursors to accumulate within the body (Figure 1).
Related Knowledge Centers
- Amine
- Aminolevulinic Acid
- Carboxylic Acid
- Coenzyme A
- Glycine
- Iron
- Pyridoxal Phosphate
- Sideroblastic Anemia
- Tetrapyrrole
- Succinyl-Coa