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The histidine brace: nature's copper alternative to haem?

ABSTRACT: The copper histidine brace is a structural unit in metalloproteins (Proc Natl Acad Sci USA 2011, 108, 15079). It consists of a copper ion chelated by the NH₂ and π-N atom of an N-terminal histidine, and the τ-N atom of a further histidine, in an overall T-shaped coordination geometry (Nat Catal 2018, 1, 571). Like haem-containing proteins, histidine-brace-containing proteins have peroxygenase and/or oxygenase activity, where the substrates are notable for resistance to oxidation, for example, lytic polysaccharide monooxygenases (LPMOs). Moreover, the histidine brace is an invariant unit around which different protein structures exert different activities. Given the similarities in the diversity of function of proteins that contain either the copper histidine brace or haem, the question arises as to whether the functions of histidine brace-containing proteins duplicate those containing haem groups.

SUBMITTER: Walton PH

PROVIDER: S-EPMC10952591 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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The histidine brace: nature's copper alternative to haem?

Walton Paul H PH Davies Gideon J GJ Diaz Daniel E DE Franco-Cairo João P JP

FEBS letters 20230129 4

The copper histidine brace is a structural unit in metalloproteins (Proc Natl Acad Sci USA 2011, 108, 15079). It consists of a copper ion chelated by the NH<sub>2</sub> and π-N atom of an N-terminal histidine, and the τ-N atom of a further histidine, in an overall T-shaped coordination geometry (Nat Catal 2018, 1, 571). Like haem-containing proteins, histidine-brace-containing proteins have peroxygenase and/or oxygenase activity, where the substrates are notable for resistance to oxidation, for ...[more]

PMID: 36660911

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Project description:BackgroundHaem is a key metabolic factor in the life cycle of the malaria parasite. In the blood stage, the parasite acquires host haemoglobin to generate amino acids for protein synthesis and the by-product haem for metabolic use. The malaria parasite can also synthesize haem de novo on its own. Plasmodium falciparum-specific histidine-rich protein 2 (PfHRP2) has a haem-binding site to mediate the formation of haemozoin, a biocrystallized form of haem aggregates. Notably, the gene regulates the mechanism of haemoglobin-derived haem metabolism and the de novo haem biosynthetic pathway in the Pfhrp2-disrupted parasite line during the intraerythrocytic stages.MethodsThe CRISPR/Cas9 system was used to disrupt the gene locus of Pfhrp2. DNA was extracted from the transgenic parasite, and PCR, Southern blotting and Western blotting were used to confirm the establishment of transgenic parasites. RNA-sequencing and comparative transcriptome analysis were performed to identify differences in gene expression between 3D7 and Pfhrp2--3D7 parasites.ResultsPfhrp2- transgenic parasites were successfully established by the CRISPR/Cas9 system. A total of 964, 1261, 3138, 1064, 2512 and 1778 differentially expressed genes (DEGs) were identified in the six comparison groups, respectively, with 373, 520, 1499, 353, 1253 and 742 of these DEGs upregulated and 591, 741, 1639, 711, 1259 and 1036 of them downregulated, respectively. Five DEGs related to haem metabolism and synthesis were identified in the comparison groups at six time points (0, 8, 16, 24, 32, and 40 h after merozoite invasion). The genes encoding delta-aminolevulinic acid synthetase and ferrochelatase, both related to haem biosynthesis, were found to be significantly upregulated in the comparison groups, and those encoding haem oxygenase, stromal-processing peptidase and porphobilinogen deaminase were found to be significantly downregulated. No GO terms were significantly enriched in haem-related processes (Q value = 1).ConclusionOur data revealed changes in the transcriptome expression profile of the Pfhrp2--3D7 parasite during the intraerythrocytic stages. The findings provide insight at the gene transcript level that will facilitate further research on and development of anti-malaria drugs.

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The histidine brace: nature's copper alternative to haem?

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The histidine brace: nature's copper alternative to haem?

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