scholarly journals Nutritional Factors That Affect the Formation of 5-Aminolevulinic Acid, a Key Intermediate of Heme Biosynthesis

2021 ◽  
Vol 67 (5) ◽  
pp. 339-350
Author(s):  
Yukiko IMI ◽  
Katsumi SHIBATA
Keyword(s):  
Aminolevulinic Acid ◽  
Heme Biosynthesis ◽  
Nutritional Factors

Dependence of heme biosynthesis on iron-sulfur cluster biogenesis: human ALAD is an unrecognized iron-sulfur protein

2020 ◽  
Author(s):  
Gang Liu ◽  
Debangsu Sil ◽  
Wing-Hang Tong ◽  
Nunziata Maio ◽  
J. Martin Bollinger ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Biosynthetic Pathway ◽  
Aminolevulinic Acid ◽  
Heme Biosynthesis ◽  
Second Step ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Sulfur Protein ◽  
Iron Sulfur Protein

Abstract Heme biosynthesis and iron-sulfur cluster (ISC) biogenesis are two major mammalian metabolic pathways that require iron. It has long been known that these two pathways interconnect, but the previously described interactions do not fully explain why heme biosynthesis depends on intact ISC biogenesis. Herein we have identified a previously unrecognized connection between these two pathways through our discovery that human aminolevulinic acid dehydratase (ALAD), which catalyzes the second step of heme biosynthesis, is an Fe-S protein. We found that several highly conserved cysteines and an Ala306-Phe307-Arg308 motif of human ALAD are important for [Fe4S4] cluster acquisition and coordination. The enzymatic activity of human ALAD was greatly reduced upon loss of its Fe-S cluster, which resulted in reduced heme biosynthesis in human cells. Our findings explain why heme biosynthesis depends on intact ISC biogenesis, as ALAD provides an early Fe-S-dependent checkpoint in the heme biosynthetic pathway.

scholarly journals Distinct Prominent Roles for Enzymes of Plasmodium berghei Heme Biosynthesis in Sporozoite and Liver Stage Maturation

2016 ◽  
Vol 84 (11) ◽  
pp. 3252-3262 ◽  
Author(s):  
Zaira Rizopoulos ◽  
Kai Matuschewski ◽  
Joana M. Haussig
Keyword(s):  
Life Cycle ◽  
De Novo ◽  
Aminolevulinic Acid ◽  
Vital Role ◽  
Heme Biosynthesis ◽  
Cycle Progression ◽  
Liver Stage ◽  
Content Type ◽  
Targeted Gene Deletion ◽  
Complex Regulation

Malarial parasites have evolved complex regulation of heme supply and disposal to adjust to heme-rich and -deprived host environments. In addition to its own pathway for heme biosynthesis,Plasmodiumlikely harbors mechanisms for heme scavenging from host erythrocytes. Elaborate compartmentalization ofde novoheme synthesis into three subcellular locations, including the vestigial plastid organelle, indicates critical roles in life cycle progression. In this study, we systematically profile the essentiality of heme biosynthesis by targeted gene deletion of enzymes in early steps of this pathway. We show that disruption of endogenous heme biosynthesis leads to a first detectable defect in oocyst maturation and sporogony in theAnophelesvector, whereas blood stage propagation, colonization of mosquito midguts, or initiation of oocyst development occurs indistinguishably from that of wild-type parasites. Although sporozoites are produced by parasites lacking an intact pathway for heme biosynthesis, they are absent from mosquito salivary glands, indicative of a vital role for heme biosynthesis only in sporozoite maturation. Rescue of the first defect in sporogony permitted analysis of potential roles in liver stages. We show that liver stage parasites benefit from but do not strictly depend upon their own aminolevulinic acid synthase and that they can scavenge aminolevulinic acid from the host environment. Together, our experimental genetics analysis ofPlasmodiumenzymes for heme biosynthesis exemplifies remarkable shifts between the use of endogenous and host resources during life cycle progression.

scholarly journals Elevated blood Lead impairs the Hematological and Heme Biosynthesis related parameters of Silver Jewellery Workers

2021 ◽  
Vol 12 (1) ◽  
pp. 662-668
Author(s):  
Mandakini S Kshirsagar ◽  
Jyotsna A Patil ◽  
Arun J Patil
Keyword(s):  
Aminolevulinic Acid ◽  
Lead Level ◽  
Blood Lead ◽  
Heme Biosynthesis ◽  
Haematological Parameters ◽  
Control Group ◽  
Healthy Male ◽  
Wbc Count ◽  
Age Range ◽  
Male Subjects

To see the present scenario of blood lead (BPb) levels of Silver Jewellery Workers (SJW) and its effects on haematological and heme biosynthesis parameters. Forty-two SJW of having an age range of 20-45 years were included for this study and compared with 50 healthy male subjects of the same age. Blood lead, RBC δ- aminolevulinic acid dehydratase (δ-ALDH), urinary δ- aminolevulinic acid (U- δ-ALA), urinary porphobilinogen (U-PBG) and haematological parameters were measured. Blood lead level of silver jewellery workers was significantly elevated (p<0.001, 325%) and non-activated δ-ALAD (p<0.01), activated δ-ALAD (p<0.05) were notably reduced and the ratio of A/NA δ-ALAD (p<0.01) was considerably enlarged in SJW as compared to control group subjects. Urinary excretion of δ-ALA (p<0.001) and PBG (p<0.001) levels were extensively increased in SJW as compared to subjects from the control group. Hb (p<0.001), PCV (p<0.001), MCV (p<0.001), MCH (p<0.05) and RBC (p<0.001) were notably reduced in SJW, while total WBC count (p<0.001, 29.8%) was considerably elevated as compared to subjects from the control group. Conclusions: Increased BPb level in SJW indicates the more absorption of lead from the GIT, which inhibits heme biosynthesis, and alters haematological parameters.

scholarly journals PILOT RESEARCH OF A GENETIC PREDISPOSITION FOR CLINICAL MANIFESTATIONS OF ACUTE INTERMITTENT PORPHYRIA

2019 ◽  
Vol 64 (2) ◽  
pp. 123-137
Author(s):  
O. S. Pshenichnikova ◽  
M. V. Goncharova ◽  
Y. S. Pustovoit ◽  
I. V. Karpova ◽  
V. L. Surin
Keyword(s):  
Aminolevulinic Acid ◽  
Clinical Manifestations ◽  
Acute Intermittent Porphyria ◽  
Severe Form ◽  
Heme Biosynthesis ◽  
Whole Exome ◽  
Number Of Patients ◽  
Detoxification Systems ◽  
Illumina Hiseq4000

Introduction. Acute intermittent porphyria (AIP) is the most common and severe form of acute hepatic porphyria. AIP is caused by a deficiency in the third enzyme of the heme biosynthesis system — hydroxymethylbilanine synthase (HMBS) — and has a dominant inheritance type. However, the probability of the clinical manifestation of this condition in carriers of the mutation in the HMBS gene constitutes only 10–20 %. Thi s suggests that the presence of such a mutation can be a necessary but not a sufficient condition for the development of the disease.Aim. To search for additional genetic factors, which determine the clinical penetrance of AIP using Whole-Exome Sequencing.Materials and methods. Sequencing of the whole exome was performed using a TruSeqExomeLibraryPrepkit (Illumina) kit by an Illumina HiSeq4000 instrument for 6 women with API with known mutations in the HMBS gene. All the patients suffered from a severe form of the disease. As a reference, a version of the hg19 human genome was used.Results. No common mutations were found in the examined patients. However, in each patient, functional variations were found in the genes related to detoxification systems, regulation of the heme biosynthesis cascade and expression of delta-aminolevulinic acid synthase (ALAS1) and in genes of proteins regulating nervous system. These variations require further study involving an extended number of patients with AIP manifestations and their relatives, who are asymptomatic carriers of disorders in the gene HMBS.Conclusions. The results obtained have allowed us to formulate a hypothesis about a possible role of genetic defects in the penetrance of AIP, which determine the development of other neurological pathologies. This is evidenced by the presence of gene pathogenic variations in 5 out of 6 examined patients, defects in which are associated with hereditary myasthenia and muscle atrophy.

scholarly journals New Insights into the Pivotal Role of Iron/Heme Metabolism in TLR4/NF-κB Signaling-Mediated Inflammatory Responses in Human Monocytes

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2549
Author(s):  
Dong Young Kang ◽  
Nipin Sp ◽  
Eun Seong Jo ◽  
Jin-Moo Lee ◽  
Kyoung-Jin Jang
Keyword(s):  
Iron Metabolism ◽  
High Glucose ◽  
Aminolevulinic Acid ◽  
Inflammatory Responses ◽  
Heme Biosynthesis ◽  
Heme Synthesis ◽  
Heme Metabolism ◽  
Inflammatory Conditions ◽  
Iron Heme

Iron metabolism and heme biosynthesis are essential processes in cells during the energy cycle. Alteration in these processes could create an inflammatory condition, which results in tumorigenesis. Studies are conducted on the exact role of iron/heme metabolism in induced inflammatory conditions. This study used lipopolysaccharide (LPS)- or high-glucose-induced inflammation conditions in THP-1 cells to study how iron/heme metabolism participates in inflammatory responses. Here, we used iron and heme assays for measuring total iron and heme. We also used flow cytometry and Western blotting to analyze molecular responses. Our results demonstrated that adding LPS or high-glucose induced iron formation and heme synthesis and elevated the expression levels of proteins responsible for iron metabolism and heme synthesis. We then found that further addition of heme or 5-aminolevulinic acid (ALA) increased heme biosynthesis and promoted inflammatory responses by upregulating TLR4/NF-κB and inflammatory cytokine expressions. We also demonstrated the inhibition of heme synthesis using succinylacetone (SA). Moreover, N-MMP inhibited LPS- or high-glucose-induced inflammatory responses by inhibiting TLR4/NF-κB signaling. Hence, iron/heme metabolism checkpoints could be considered a target for treating inflammatory conditions.

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