Phospholipase D: Enzymology, Functionality, and Chemical Modulation

Selvy, Paige E.; Lavieri, Robert R.; Lindsley, Craig W.; Brown, H. Alex

doi:10.1021/cr200296t

Cited by 332 publications

(478 citation statements)

References 569 publications

(1,624 reference statements)

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“…In contrast to the previously discussed RNA nucleases, Zuc does not employ a canonical RNase fold. Rather, Zuc belongs to the HKD family of phosphodiesterases, named for its conserved His-Lys-Asp residues in and near the active site [48]. The HKD motif has been appropriated by phospholipases and nucleases alike, performing hydrolysis in a cationindependent fashion.…”

Section: Other Components Of Micro and Sirna Biogenesismentioning

confidence: 99%

From guide to target: molecular insights into eukaryotic RNA-interference machinery

Ipsaro

Joshua‐Tor

2015

Nat Struct Mol Biol

216

144

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Since its relatively recent discovery, RNA interference (RNAi) has emerged as a potent, specific, and ubiquitous means of gene regulation. Through a number of pathways that are conserved from yeast to humans, small non-coding RNAs direct molecular machinery to silence gene expression. In this review, we focus on mechanisms and structures that govern RNA silencing in higher organisms. In addition to highlighting recent advances, parallels and differences between RNAi pathways are discussed. Together, the studies reviewed herein reveal the versatility and programmability of RNA-induced Silencing Complexes (RISCs) and emphasize the importance of both upstream biogenesis and downstream silencing factors. Discovery and Biological Perspectives of RNA interferenceRNAi was first described by Fire and Mello in the 1990s when, in an attempt to use antisense RNA to down-regulate gene expression, they observed that double-stranded RNA (dsRNA) was more potent than sense or anti-sense RNA alone [1]. This seminal work boasted robust and specific gene knock down in addition to coining the term "RNA interference" (RNAi). Shortly beforehand, the discovery of individual regulatory RNAs in C. elegans hinted that small, non-coding RNAs might be a pervasive means of gene regulation in higher organisms [2,3]. In the following decade, with the mechanistic insight of Fire and Mello's work in hand, this idea was confirmed and it is now accepted that wellover 1,000 small RNAs are encoded in the human genome that may regulate over 60% of our genes [4,5]. It also became apparent that several seemingly disconnected phenomena are variations of RNAi-type pathways including co-suppression in plants, DNA elimination in Tetrahymena, and quelling in Neurospora [6]. The prevalence of RNAi is impressive and its importance is underscored by the fact that RNAi dysfunction is associated with numerous diseases and disorders including neurological maladies, cancers, and infertility.Shortly after the initial description of RNAi phenomenology, a burst of genetic, biochemical, biophysical, and bioinformatic efforts laid a strong foundation for identifying the molecular pathways, players, and parameters that govern silencing via RNAi. Work from Reprints and permissions information is available online at http://www.nature.com/reprints/index.html. HHMI Author ManuscriptHHMI Author Manuscript HHMI Author Manuscript numerous groups defined the molecular apparatus of RNAi as RISC (RNA-induced Silencing Complex), a ribonucleoprotein complex minimally comprised of a small singlestranded RNA (~20-31 nucleotides) and an Argonaute protein which serves as the effector molecule (reviewed in [7]). In this configuration, the loaded "guide" RNA acts as a specificity determinant that directs Argonaute and any other associated machinery to the target. The guide-loaded Argonaute platform underlies every example in the expansive array of known RNAi pathways in eukaryotes regardless of the source of the guide (structured loci, transposons, viral, etc.), the machinery ...

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Section: Other Components Of Micro and Sirna Biogenesismentioning

confidence: 99%

From guide to target: molecular insights into eukaryotic RNA-interference machinery

Ipsaro

Joshua‐Tor

2015

Nat Struct Mol Biol

216

144

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“…Briefly, cells were seeded at 300,000 cells/well into 6-well tissue culture plates, and designed experiments were carried out in the presence or absence of 0.3% 1-BuOH-d 10 for the desired times. At the end of the stimulation, plates were placed on ice, and media were aspirated.…”

Section: Pld Endogenous Assaysmentioning

confidence: 99%

“…Primary alco-hols have long been used as tools to block PLD-generated PA production (10,38). In the presence of primary alcohols PLD carries out a preferred transphosphatidylation reaction resulting in the production of phosphatidyl alcohols rather than phosphatidic acid (39 -41).…”

Section: Udp Stimulation Of the P2ymentioning

confidence: 99%

“…Effects of 1-butanol addition on PA and PtdBuOH production. PA and PtdBuOH levels were measured after a 30-min stimulation of 1321N1-P2Y 6 cells with 100 M UDP either in the presence or absence of 0.3% 1-butanol-d 10 . After stimulation, cellular lipids were extracted and analyzed by LC-MS to quantitate lipid levels.…”

Section: Udp Stimulation Of the P2ymentioning

confidence: 99%

“…Our laboratories have developed dual PLD1/2 inhibitors (VU0155056), a 1700-fold PLD1-specific inhibitor (VU0359595), and a 75-fold PLD2 preferring inhibitor (VU0364739) to better understand the therapeutic potential of these enzymes. Currently, PLD inhibitors are being evaluated for their potential use in brain disorders such as Alzheimer disease and stroke (21), chronic inflammation (22), and cancer (10,23,24).…”

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confidence: 99%

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Regulation of Phospholipase D Activity and Phosphatidic Acid Production after Purinergic (P2Y6) Receptor Stimulation

Scott¹,

Xiang²,

Mathews³

et al. 2013

Journal of Biological Chemistry

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Background: Phosphatidic acid is a key lipid second messenger often generated after receptor stimulation. Results: After P2Y 6 receptor stimulation both PLD and DGK enzymes are responsible for producing PA species. Conclusion: DGK facilitates a negative regulation of PLD and tightly controls PA levels. Significance: Further understanding the PA signaling network is critical to developing next generation therapeutics for human diseases.

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Phosphatidic acid in membrane rearrangements

et al. 2019

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Phosphatidic acid (PA) is the simplest cellular glycerophospholipid characterized by unique biophysical properties: a small headgroup; negative charge; and a phosphomonoester group. Upon interaction with lysine or arginine, PA charge increases from −1 to −2 and this change stabilizes protein–lipid interactions. The biochemical properties of PA also allow interactions with lipids in several subcellular compartments. Based on this feature, PA is involved in the regulation and amplification of many cellular signalling pathways and functions, as well as in membrane rearrangements. Thereby, PA can influence membrane fusion and fission through four main mechanisms: it is a substrate for enzymes producing lipids (lysophosphatidic acid and diacylglycerol) that are involved in fission or fusion; it contributes to membrane rearrangements by generating negative membrane curvature; it interacts with proteins required for membrane fusion and fission; and it activates enzymes whose products are involved in membrane rearrangements. Here, we discuss the biophysical properties of PA in the context of the above four roles of PA in membrane fusion and fission.

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Phospholipase D: Enzymology, Functionality, and Chemical Modulation

Cited by 332 publications

References 569 publications

From guide to target: molecular insights into eukaryotic RNA-interference machinery

From guide to target: molecular insights into eukaryotic RNA-interference machinery

Regulation of Phospholipase D Activity and Phosphatidic Acid Production after Purinergic (P2Y6) Receptor Stimulation

Phosphatidic acid in membrane rearrangements

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