Substrate Efflux Propensity Is the Key Determinant of Ca2+-independent Phospholipase A-β (iPLAβ)-mediated Glycerophospholipid Hydrolysis

Batchu, Krishna Chaithanya; Hokynar, Kati; Jeltsch, Michael; Mattonet, Kenny; Somerharju, Pentti

doi:10.1074/jbc.m115.642835

Cited by 10 publications

(15 citation statements)

References 72 publications

(71 reference statements)

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“…Consistently, we have recently shown that PNPLA9, -6 and -4 catalyze homeostatic degradation of PC, PE and PS in human cells (26). More importantly, we have provided strong evidence that the activity of PNPLA9 in vitro is proportional to the propensity of its GPL substrate to efflux from the membrane (27), consistent with the prediction that the active site of PNPLA9 resides well above the membrane surface (28). Since the efflux propensity of a GPL molecule should be proportional to its chemical activity, we propose that homeostatic degradation of GPLs in mammalian cells depends on their chemical activity.…”

Section: Increased Chemical Activity Renders Gpls Susceptible To Hydrsupporting

confidence: 83%

Hypothesis: Chemical Activity Regulates and Coordinates the Process Maintaining Glycerophospholipid Homeostasis in Mammalian Cells.

Somerharju¹,

Virtanen²,

Hermansson³

2019

Preprint

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Mammalian cells maintain the complex glycerophospholipid (GPL) class compositions of their various membranes within close limits because this is essential to their well-being or viability. Surprisingly, however it is still not understood how those compositions are maintained except that GPL synthesis and degradation closely coordinated. Here, we hypothesize that abrupt changes in the chemical activity of the individual GPL classes coordinate the synthesis and degradation, as well other homeostatic processes. A previously proposed model proposed that in cellular membranes only a limited number of “allowed” or optimal GPL glass compositions exist because they are energetically more favorable than the other compositions, i.e. they represent local free energy minima (Somerharju et al. 2009). This model, however, could not satisfactorily explain how the optimal compositions are sensed by the key homeostatic enzymes i.e., the rate-limiting synthetizing enzymes and the degrading enzymes (i.e., homeostatic phospholipases). We now propose that when the mole fraction of a GPL class exceeds an optimal one, its chemical activity abruptly increases, which (i) increases its propensity to efflux from the membrane thus making it susceptible for hydrolysis by homeostatic phospholipases, (ii) increases its potency to inhibit its own biosynthesis via a feedback mechanism, (iii) enhances its conversion to another GPL class via a novel process termed “head group remodeling” or (iv) enhances its translocation to other subcellular membranes. Accordingly, abrupt changes in the chemical activity of the individual GPL classes is proposed to regulate and coordinate those four processes maintaining GPL class homeostasis in mammalian cells.

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Section: Increased Chemical Activity Renders Gpls Susceptible To Hydrsupporting

confidence: 83%

Hypothesis: Chemical Activity Regulates and Coordinates the Process Maintaining Glycerophospholipid Homeostasis in Mammalian Cells.

Somerharju¹,

Virtanen²,

Hermansson³

2019

Preprint

Self Cite

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show abstract

“…Consistently, we have recently shown that PNPLA9, −6, and −4 catalyze homeostatic degradation of PC, PE, and PS in human cells . More importantly, we have provided strong evidence that the activity of PNPLA9 in vitro is proportional to the propensity of its GPL substrate to efflux from the membrane to the active site of PNPLA9, predicted to reside well above the membrane surface . Since the efflux propensity of a GPL molecule should be proportional to its chemical activity, we propose that the rate of homeostatic degradation of GPLs correlates positively on their chemical activity.…”

Section: Introductionsupporting

confidence: 82%

Hypothesis: Chemical activity regulates and coordinates the processes maintaining glycerophospholipid homeostasis in mammalian cells

2020

Self Cite

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Mammalian cells maintain the complex glycerophospholipid (GPL) class compositions of their various membranes within close limits because this is essential to their well‐being or viability. Surprisingly, however, it is still not understood how those compositions are maintained except that GPL synthesis and degradation are closely coordinated. Here, we hypothesize that abrupt changes in the chemical activity of the individual GPL classes coordinate synthesis and degradation as well other the homeostatic processes. We have previously proposed that only a limited number of “allowed” or “optimal” GPL class compositions exist in cellular membranes because those compositions are energetically more favorable than others, that is, they represent local free energy minima (Somerharju et al 2009, Biochim. Biophys. Acta 1788, 12‐23). This model, however, could not satisfactorily explain how the “optimal” compositions are sensed by the key homeostatic enzymes, that is, rate‐limiting synthetizing enzymes and homeostatic phospholipases. We now hypothesize that when the mole fraction of a GPL class exceeds an optimal value, its chemical activity abruptly increases which (a) increases its propensity to efflux from the membrane thus making it susceptible for hydrolysis by homeostatic phospholipases; (b) increases its potency to inhibit its own biosynthesis via a feedback mechanism; (c) enhances its conversion to another glycerophospholipid class via a novel process termed “head group remodeling” or (d) enhances its translocation to other subcellular membranes. In summary, abrupt change in the chemical activity of the individual GPL classes is proposed to regulate and coordinate those four processes maintaining GPL class homeostasis in mammalian cells.

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“…The phospholipase substrate preferences partly arise from the placement of the PUFA precursors in different molecular species of membrane GPLs. In addition to the reported preferences to hydrolyze a specific sn-2 acyl chain (e.g., 20:4n-6 by cPLA 2 IV), the sn-1 acyl chain also affects the rate of GPL species hydrolysis due to the different degree of hydrophilicities and efflux propensities of different GPL species from the membrane bilayer (66)(67)(68). Functional consequences follow since Dong et al (51) found that the coadministered nonessential fatty acids, 16:0, 18:1n-9, and 18:0 stimulated 20:4n-6-derived COX-2 activity, and the highest stimulation was recorded with the combination 16:0/20:4n-6, which species was kept as a minor component of the PC and PE of hBMSCs.…”

Section: Discussionmentioning

confidence: 99%

Metabolism and phospholipid assembly of polyunsaturated fatty acids in human bone marrow mesenchymal stromal cells

Tigistu-Sahle

Lampinen

Kilpinen

et al. 2017

Journal of Lipid Research

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Substrate Efflux Propensity Is the Key Determinant of Ca2+-independent Phospholipase A-β (iPLAβ)-mediated Glycerophospholipid Hydrolysis

Cited by 10 publications

References 72 publications

Hypothesis: Chemical Activity Regulates and Coordinates the Process Maintaining Glycerophospholipid Homeostasis in Mammalian Cells.

Hypothesis: Chemical Activity Regulates and Coordinates the Process Maintaining Glycerophospholipid Homeostasis in Mammalian Cells.

Hypothesis: Chemical activity regulates and coordinates the processes maintaining glycerophospholipid homeostasis in mammalian cells

Metabolism and phospholipid assembly of polyunsaturated fatty acids in human bone marrow mesenchymal stromal cells

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