The radical SAM protein HemW is a heme chaperone

Haskamp, Vera; Karrie, Simone; Mingers, Toni; Barthels, Stefan; Alberge, François; Magalon, Axel; Müller, Katrin; Bill, Eckhard; Lubitz, Wolfgang; Kleeberg, Kirstin; Schweyen, Peter; Bröring, Martin; Jahn, Martina; Jahn, Dieter

doi:10.1074/jbc.ra117.000229

Cited by 35 publications

(40 citation statements)

References 41 publications

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“…The cytosolic tRNA modification factor Tyw5 associates with iron and was also drastically reduced after iron deprivation. A slight downregulation was noted for ISC-containing cytosolic Irp1/Aco1 and for ISC-containing Rsad1, which is a heme chaperone in the mitochondrial matrix [108]. In contrast, ISC-containing Rsad2 at the mitochondrial outer membrane and the endoplasmic reticulum [109] was not exhibiting dysregulation in MEF after iron manipulation, despite previous reports on its Pink1-dependence in immune responses [29].…”

Section: Discussionmentioning

confidence: 70%

Iron Depletion Reduces Abce1 Transcripts While Inducing the Mitophagy Factors Pink1 and Parkin

Key¹,

Sen²,

Arsovic³

et al. 2019

Preprint

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Lifespan extension was recently achieved in Caenorhabditis elegans nematodes by mitochondrial stress and mitophagy, triggered via iron depletion. Conversely in man, deficient mitophagy due to Pink1/Parkin mutations triggers iron accumulation in patient brain and limits survival. We now aimed to identify murine fibroblast factors, which adapt their mRNA expression to acute iron manipulation, relate to mitochondrial dysfunction and may influence survival. After iron depletion, expression of the plasma membrane receptor Tfrc with its activator Ireb2, the mitochondrial membrane transporter Abcb10, the heme-release factor Pgrmc1, the heme-degradation enzyme Hmox1, the heme-binding cholesterol metabolizer Cyp46a1, as well as the mitophagy regulators Pink1 and Parkin showed a negative correlation to iron levels. After iron overload, these factors did not change expression. Conversely, a positive correlation of mRNA levels with both conditions of iron availability was observed for the endosomal factors Slc11a2 and Steap2, as well as for the iron-sulfur-cluster (ISC)-containing factors Ppat, Bdh2 and Nthl1. Positive correlation only after iron depletion was observed for the iron export factor Slc40a1, mitochondrial iron transporters Slc25a28, Abcb7 and Abcb8, mitochondrial ISC-containing factors Glrx5, Nfu1, Bola1 and Abce1, cytosolic Aco1 and Tyw5, as well as nuclear Dna2, Elp3, Pold1 and Prim2. The latter are regulators of nucleotide synthesis and DNA quality control, which have known importance for growth and lifespan. The only Pink1-/- triggered transcript modulation was the reduced expression of the ISC-containing ribosomal factor Abce1. These mammalian findings support previous fly data that Pink1 influences co-translational quality control via Abce1, as well as mitophagy. Our findings provide the first systematic survey how iron dosage triggers homeostatic transcriptional regulations and elucidate how iron deprivation results in mitophagy.

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Section: Discussionmentioning

confidence: 70%

Iron Depletion Reduces Abce1 Transcripts While Inducing the Mitophagy Factors Pink1 and Parkin

Key¹,

Sen²,

Arsovic³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The cytosolic tRNA modification factor TYW5 associates with iron and was also clearly reduced after iron deprivation. A downregulation was noted for ISC-containing cytosolic IRP1/ Aco1 as well as for ISC-containing Rsad1 (in PINK1-deficient cells), which encodes a heme chaperone in the mitochondrial matrix [ 140 ]. However, ISC-containing FECH in mitochondria did not show relevant expression dysregulation.…”

Section: Discussionmentioning

confidence: 99%

Systematic Surveys of Iron Homeostasis Mechanisms Reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence

Key

Sen

Arsovic

et al. 2020

Cells

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Iron deprivation activates mitophagy and extends lifespan in nematodes. In patients suffering from Parkinson’s disease (PD), PINK1-PRKN mutations via deficient mitophagy trigger iron accumulation and reduce lifespan. To evaluate molecular effects of iron chelator drugs as a potential PD therapy, we assessed fibroblasts by global proteome profiles and targeted transcript analyses. In mouse cells, iron shortage decreased protein abundance for iron-binding nucleotide metabolism enzymes (prominently XDH and ferritin homolog RRM2). It also decreased the expression of factors with a role for nucleotide surveillance, which associate with iron-sulfur-clusters (ISC), and are important for growth and survival. This widespread effect included prominently Nthl1-Ppat-Bdh2, but also mitochondrial Glrx5-Nfu1-Bola1, cytosolic Aco1-Abce1-Tyw5, and nuclear Dna2-Elp3-Pold1-Prim2. Incidentally, upregulated Pink1-Prkn levels explained mitophagy induction, the downregulated expression of Slc25a28 suggested it to function in iron export. The impact of PINK1 mutations in mouse and patient cells was pronounced only after iron overload, causing hyperreactive expression of ribosomal surveillance factor Abce1 and of ferritin, despite ferritin translation being repressed by IRP1. This misregulation might be explained by the deficiency of the ISC-biogenesis factor GLRX5. Our systematic survey suggests mitochondrial ISC-biogenesis and post-transcriptional iron regulation to be important in the decision, whether organisms undergo PD pathogenesis or healthy aging.

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“…In 2018, Haskamp et al. 57 reported that HemW harbors two SAM molecules and a [4Fe-4S] cluster, and is present as a dimer upon cluster binding. They also found that HemW functions in heme trafficking, triggering the release of heme from HemW in the presence of membranes and acting as a heme chaperone 57 , 58 .…”

Section: Nonmethylation Reactions Catalyzed By Sam-dependent Enzymesmentioning

confidence: 99%

“… 57 reported that HemW harbors two SAM molecules and a [4Fe-4S] cluster, and is present as a dimer upon cluster binding. They also found that HemW functions in heme trafficking, triggering the release of heme from HemW in the presence of membranes and acting as a heme chaperone 57 , 58 . Additionally, NirJ, AhbC/D, and CgdH also catalyze oxidative decarboxylation or assist the reaction with the aid of two SAM molecules and a [4Fe-4S] cluster 59 , 60 .…”

Section: Nonmethylation Reactions Catalyzed By Sam-dependent Enzymesmentioning

confidence: 99%

Diversity of the reaction mechanisms of SAM-dependent enzymes

Sun

Huang

Wei

2021

Acta Pharmaceutica Sinica B

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S -adenosylmethionine (SAM) is ubiquitous in living organisms and is of great significance in metabolism as a cofactor of various enzymes. Methyltransferases (MTases), a major group of SAM-dependent enzymes, catalyze methyl transfer from SAM to C, O, N, and S atoms in small-molecule secondary metabolites and macromolecules, including proteins and nucleic acids. MTases have long been a hot topic in biomedical research because of their crucial role in epigenetic regulation of macromolecules and biosynthesis of natural products with prolific pharmacological moieties. However, another group of SAM-dependent enzymes, sharing similar core domains with MTases, can catalyze nonmethylation reactions and have multiple functions. Herein, we mainly describe the nonmethylation reactions of SAM-dependent enzymes in biosynthesis. First, we compare the structural and mechanistic similarities and distinctions between SAM-dependent MTases and the non-methylating SAM-dependent enzymes. Second, we summarize the reactions catalyzed by these enzymes and explore the mechanisms. Finally, we discuss the structural conservation and catalytical diversity of class I-like non-methylating SAM-dependent enzymes and propose a possibility in enzymes evolution, suggesting future perspectives for enzyme-mediated chemistry and biotechnology, which will help the development of new methods for drug synthesis.

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The radical SAM protein HemW is a heme chaperone

Cited by 35 publications

References 41 publications

Iron Depletion Reduces Abce1 Transcripts While Inducing the Mitophagy Factors Pink1 and Parkin

Iron Depletion Reduces Abce1 Transcripts While Inducing the Mitophagy Factors Pink1 and Parkin

Systematic Surveys of Iron Homeostasis Mechanisms Reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence

Diversity of the reaction mechanisms of SAM-dependent enzymes

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