Regulations of myo-inositol homeostasis: Mechanisms, implications, and perspectives

Xue, Shaowu; Ko, An-Li Andrea; Saiardi, Adolfo

doi:10.1016/j.jbior.2022.100921

Cited by 21 publications

(11 citation statements)

References 100 publications

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“…This dephosphorylation could potentially proceed all the way to myo -inositolwith the aid of additional phosphataseswhich could then be released through inositol transporters like SLC2A13 (HMIT). HMIT is known to be localized in intracellular membranes due to its ER-retention sequence and internalization sequence. ,,− …”

Section: Discussionmentioning

confidence: 99%

Stable Isotopomers of myo-Inositol Uncover a Complex MINPP1-Dependent Inositol Phosphate Network

et al. 2022

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The water-soluble inositol phosphates (InsPs) represent a functionally diverse group of small-molecule messengers involved in a myriad of cellular processes. Despite their centrality, our understanding of human InsP metabolism is incomplete because the available analytical toolset to characterize and quantify InsPs in complex samples is limited. Here, we have synthesized and applied symmetrically and unsymmetrically 13 C-labeled myo-inositol and inositol phosphates. These probes were utilized in combination with nuclear magnetic resonance spectroscopy (NMR) and capillary electrophoresis mass spectrometry (CE-MS) to investigate InsP metabolism in human cells. The labeling strategy provided detailed structural information via NMR�down to individual enantiomers�which overcomes a crucial blind spot in the analysis of InsPs. We uncovered a novel branch of InsP dephosphorylation in human cells which is dependent on MINPP1, a phytase-like enzyme contributing to cellular homeostasis. Detailed characterization of MINPP1 activity in vitro and in cells showcased the unique reactivity of this phosphatase. Our results demonstrate that metabolic labeling with stable isotopomers in conjunction with NMR spectroscopy and CE-MS constitutes a powerful tool to annotate InsP networks in a variety of biological contexts.

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Section: Discussionmentioning

confidence: 99%

Stable Isotopomers of myo-Inositol Uncover a Complex MINPP1-Dependent Inositol Phosphate Network

et al. 2022

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“…Moreover, how does myo-Ins supplementation modify the complex inositol-related network, and how could inositol-related metabolites influence the overall picture? To obtain a reliable picture, we should be able to capture the whole metabolic fate of myo-Ins when added to a specific tissue/cellular context and correlate changes in inositol metabolism with the associated biochemical pathways [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

“…In humans, myo-Ins (~1 g/day) primarily comes from dietary intake, albeit a relevant fraction is synthesized endogenously, in a variable range (from 1 to 4 g/day), depending on several factors, yet requiring a full assessment [ 45 ]. Within the mammalian cell, myo-Ins is synthesized from glucose-6-phosphate (G6P), which is isomerized to inositol-3-phosphate (Ins-(3)-P) by D-3-myo-inositol-phosphate synthase (inositol synthase, MIPS1) [ 46 ], encoded by the inositol-3-phosphate synthase 1 (ISYNA1) gene [ 47 ]. Then, inositol monophosphatase-1 (IMPA1 or IMPase) dephosphorylates Ins-(3)-P to release free myo-Ins [ 48 ].…”

Section: Inositols In Mammalsmentioning

confidence: 99%

The Role of Inositols in the Hyperandrogenic Phenotypes of PCOS: A Re-Reading of Larner’s Results

Fedeli

Catizone

Querqui

et al. 2023

IJMS

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Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women, in which, besides chronic anovulation/oligomenorrhea and ovarian cysts, hyperandrogenism plays a critical role in a large fraction of subjects. Inositol isomers—myo-Inositol and D-Chiro-Inositol—have recently been pharmacologically effective in managing many PCOS symptoms while rescuing ovarian fertility. However, some disappointing clinical results prompted the reconsideration of their specific biological functions. Surprisingly, D-Chiro-Ins stimulates androgen synthesis and decreases the ovarian estrogen pathway; on the contrary, myo-Ins activates FSH response and aromatase activity, finally mitigating ovarian hyperandrogenism. However, when the two isomers are given in association—according to the physiological ratio of 40:1—patients could benefit from myo-Ins enhanced FSH and estrogen responsiveness, while taking advantage of the insulin-sensitizing effects displayed mostly by D-Chiro-Ins. We need not postulate insulin resistance to explain PCOS pathogenesis, given that insulin hypersensitivity is likely a shared feature of PCOS ovaries. Indeed, even in the presence of physiological insulin stimulation, the PCOS ovary synthesizes D-Chiro-Ins four times more than that measured in control theca cells. The increased D-Chiro-Ins within the ovary is detrimental in preserving steroidogenic control, and this failure can easily explain why treatment strategies based upon high D-Chiro-Ins have been recognized as poorly effective. Within this perspective, two factors emerge as major determinants in PCOS: hyperandrogenism and reduced aromatase expression. Therefore, PCOS could no longer be considered a disease only due to increased androgen synthesis without considering the contemporary downregulation of aromatase and FSH receptors. Furthermore, these findings suggest that inositols can be specifically effective only for those PCOS phenotypes featured by hyperandrogenism.

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“…Many different phytase enzymes have evolved and are primarily expressed by bacteria, fungi, and plants. Animal phytases are also important for the regulation of myo-inositol and its various derivatives, which are important cell signaling molecules ( Su et al, 2023 ). Phytases can be broadly categorised into four structurally distinct classes: Histidine Acid Phytases (HAPhys), β-Propeller Phytases (BPPhys/alkaline phytases), Protein Tyrosine Phosphatase-like phytases (PTPhys/cysteine phytases), and Purple Acid Phytases (PAPhys).…”

Section: Introductionmentioning

confidence: 99%

Structural and functional profile of phytases across the domains of life

Scott,

Koh,

Rix

2024

Current Research in Structural Biology

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Regulations of myo-inositol homeostasis: Mechanisms, implications, and perspectives

Cited by 21 publications

References 100 publications

Stable Isotopomers of myo-Inositol Uncover a Complex MINPP1-Dependent Inositol Phosphate Network

Stable Isotopomers of myo-Inositol Uncover a Complex MINPP1-Dependent Inositol Phosphate Network

The Role of Inositols in the Hyperandrogenic Phenotypes of PCOS: A Re-Reading of Larner’s Results

Structural and functional profile of phytases across the domains of life

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