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Contents 1 Phosphomannose mutase 2 1.1 Background 2 Structure 3 How does PMM2 work?

Phosphomannose mutase 2

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Background

. The exploration of one of the inheritance disorders, CDG (Congenital disorder of glycosylation), reveals the fact that having defects in one copy of the genes, we could have a whole spectrum of disorders manifestations in individuals, ranging from mild to severe clinical complications. The protein which comes to the spotlight with the disorder is none of the others but the phosphomannose mutase 2 (PMM2). Since it has the function of shuffling the phosphoryl group, thus converting mannose-6-phosphate into mannose-1-phosphate (the building block for oligosaccharides for glycoproteins), it’s said to closely resemble the function of phosphoglucomutase, that PMMs are known as PGM (phosphoglucomutase) (Chuang et al, 2010). It’s reasonable to think about PMM2 to work in the same way as phosphoglucomutase does, by changing the phosphorylated position; still, the machinery of how the protein works remains mysterious. Through the exploration of its paralog, PMM1, we could then figure out bits by bits about PMM2’s structure and look at how the protein’s defects could impact on the body systems, evolutionary mutations that cause the difference of its function compared to PMM1, the clinical manifestations, and the potential manipulation of PMM2 in pharmaceutical field in the future. Phosphomannose mutase 2 is an cytosolic enzyme which is critical in the conversion of mannose-6-phosphate into mannose-1-phosphate. It's a homodimeric protein, having two identical subunits working as independent domains. It's a typical HAD superfamily protein, which has the characteristic "cap" and "core" domains.

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Structure

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PMM2 is a 246 amino acid long protein, with 2 identical subunits working as independent domains, hence it’s also known as a homodimeric protein. In addition, it’s classified as the member of HAD (haloacid dehydrolase) superfamily due to the fact that it had 4 different types of motifs, each of which is highly conserved across the vertebrates’ lineages during evolutions. Similar to other members in HAD superfamily, the two domains are separately recognized as core and cap domain. The core domain (residues 1 – 90, and 198-262)of PMM2 displays the characteristic 4 motifs of HAD superfamily that contribute to the catalytic ability of the active sites in the protein. Motif 1 has Asp as nucleophile which serves as the mediator for the phosphoryl group transfer, the second Asp, on the other hand, acts as in the general acid-base reaction. While motif 1 provides the nucleophilic and general acid-base reactions, motif 2 in the protein which usually contains Thr or Ser helps in positioning or binding on the substrates’ phosphoryl group. In addition, motif 3 has the typical Lys or Arg residues while motif 4 has the acidic residues (Asp and Glu) that bind magnesium cofactor. The cap domain of PMM2 is smaller, functioning as the regulator for the access of the substrate into the active site of the core domain and at the same time contains the primary and secondary substrate specificity loops that recognize only specific substrate.

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How does PMM2 work?

PMM2 converts mannose-6-phosphate into mannose-1-phosphate that would then serve as the building bloc of the dolichol-linked oligosaccharides for glycosylation in endoplasmic reticulum. It's not clear how PMM2 the cap and core domains would coordinate with each other. However,through the extrapolation of its paralogous protein, PMM1 which has a complex mechanism that uses charges of the conserved residues in the cap domains to sweep the substrate into core domain, we could postulate that PMM2 would utilize similar machinery. Also, with the close resemblance to the PGM proteins, PMM2 might have similar machinery that manipulate the conformational changes that “closes” cap domain after binding substrates to allow the specificity loops getting into contact with the active site of the core domain, thus participating in catalysis.