Phospholipase D inhibition

Beneficial and harmful consequences for a double-dealer enzyme

Giovanni Auricchio, Fabiola D'Aquilio, Valerio Chiurchiù, Giorgio Mancino, Patrizia M. Baldini

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

One of the most promising strategies for drug design and development is the identification of new molecules able to selectively inhibit those enzymes involved in pathological processes, without affecting other enzymes associated with physiological functions. Nevertheless, some enzymes can show a double-edge aspect of their own inhibition, which can lead to positive as well as negative consequences according to the pathological state. Phospholipase D (PLD), an ubiquitous enzyme nowadays considered as a critical regulator of several aspects of cell biology and signal transduction pathways, is a clear example of those double-dealer enzymes. While a great deal has been learned about PLD structure, biological functions and activation/regulation mechanisms, little yet is known about the derivable effects of its potential negative regulation, also due to the lack of specific inhibitors. Multiple evidences on PLD involvement in many pathological states development and progression, including inflammation, carcinogenesis and metastases, have been supplied, so that a deregulation of its activity could contribute to attenuate or slow down the inflammatory and tumour formation/progression processes. On the other hand, in agreement with other previous observations, we have recently demonstrated the direct contribution of PLD activation in promoting intracellular mycobacterial killing. In this case, PLD inhibition resulted in a significant reduction of antimicrobial innate immune response and, hence, in a possible harmful effect. In the light of the above reported considerations, besides the recent advances in characterising new compounds able to selectively inhibit PLD activity and/or signalling, this review aimed at elucidating the potential dual beneficial/harmful consequences of PLD activity modulation.

Original languageEnglish
Pages (from-to)309-333
Number of pages25
JournalCurrent Enzyme Inhibition
Volume3
Issue number4
DOIs
Publication statusPublished - Nov 2007

Fingerprint

Phospholipase D
Enzymes
4 alpha-glucanotransferase
Chemical activation
Cytology
Signal transduction
Deregulation
Drug Design
Pathologic Processes
Innate Immunity
Cell Biology
Tumors
Signal Transduction
Carcinogenesis
Modulation
Neoplasm Metastasis
Inflammation
Molecules
Pharmaceutical Preparations

Keywords

  • Inflammation
  • Inhibition
  • Oxidative burst
  • Phagocytosis
  • Phospholipase D
  • Tuberculosis
  • Tumour

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Drug Discovery

Cite this

Phospholipase D inhibition : Beneficial and harmful consequences for a double-dealer enzyme. / Auricchio, Giovanni; D'Aquilio, Fabiola; Chiurchiù, Valerio; Mancino, Giorgio; Baldini, Patrizia M.

In: Current Enzyme Inhibition, Vol. 3, No. 4, 11.2007, p. 309-333.

Research output: Contribution to journalArticle

Auricchio, Giovanni ; D'Aquilio, Fabiola ; Chiurchiù, Valerio ; Mancino, Giorgio ; Baldini, Patrizia M. / Phospholipase D inhibition : Beneficial and harmful consequences for a double-dealer enzyme. In: Current Enzyme Inhibition. 2007 ; Vol. 3, No. 4. pp. 309-333.
@article{4602f02c881841c7b5a32f8a8121b959,
title = "Phospholipase D inhibition: Beneficial and harmful consequences for a double-dealer enzyme",
abstract = "One of the most promising strategies for drug design and development is the identification of new molecules able to selectively inhibit those enzymes involved in pathological processes, without affecting other enzymes associated with physiological functions. Nevertheless, some enzymes can show a double-edge aspect of their own inhibition, which can lead to positive as well as negative consequences according to the pathological state. Phospholipase D (PLD), an ubiquitous enzyme nowadays considered as a critical regulator of several aspects of cell biology and signal transduction pathways, is a clear example of those double-dealer enzymes. While a great deal has been learned about PLD structure, biological functions and activation/regulation mechanisms, little yet is known about the derivable effects of its potential negative regulation, also due to the lack of specific inhibitors. Multiple evidences on PLD involvement in many pathological states development and progression, including inflammation, carcinogenesis and metastases, have been supplied, so that a deregulation of its activity could contribute to attenuate or slow down the inflammatory and tumour formation/progression processes. On the other hand, in agreement with other previous observations, we have recently demonstrated the direct contribution of PLD activation in promoting intracellular mycobacterial killing. In this case, PLD inhibition resulted in a significant reduction of antimicrobial innate immune response and, hence, in a possible harmful effect. In the light of the above reported considerations, besides the recent advances in characterising new compounds able to selectively inhibit PLD activity and/or signalling, this review aimed at elucidating the potential dual beneficial/harmful consequences of PLD activity modulation.",
keywords = "Inflammation, Inhibition, Oxidative burst, Phagocytosis, Phospholipase D, Tuberculosis, Tumour",
author = "Giovanni Auricchio and Fabiola D'Aquilio and Valerio Chiurchi{\`u} and Giorgio Mancino and Baldini, {Patrizia M.}",
year = "2007",
month = "11",
doi = "10.2174/157340807782330255",
language = "English",
volume = "3",
pages = "309--333",
journal = "Current Enzyme Inhibition",
issn = "1573-4080",
publisher = "Bentham Science Publishers B.V.",
number = "4",

}

TY - JOUR

T1 - Phospholipase D inhibition

T2 - Beneficial and harmful consequences for a double-dealer enzyme

AU - Auricchio, Giovanni

AU - D'Aquilio, Fabiola

AU - Chiurchiù, Valerio

AU - Mancino, Giorgio

AU - Baldini, Patrizia M.

PY - 2007/11

Y1 - 2007/11

N2 - One of the most promising strategies for drug design and development is the identification of new molecules able to selectively inhibit those enzymes involved in pathological processes, without affecting other enzymes associated with physiological functions. Nevertheless, some enzymes can show a double-edge aspect of their own inhibition, which can lead to positive as well as negative consequences according to the pathological state. Phospholipase D (PLD), an ubiquitous enzyme nowadays considered as a critical regulator of several aspects of cell biology and signal transduction pathways, is a clear example of those double-dealer enzymes. While a great deal has been learned about PLD structure, biological functions and activation/regulation mechanisms, little yet is known about the derivable effects of its potential negative regulation, also due to the lack of specific inhibitors. Multiple evidences on PLD involvement in many pathological states development and progression, including inflammation, carcinogenesis and metastases, have been supplied, so that a deregulation of its activity could contribute to attenuate or slow down the inflammatory and tumour formation/progression processes. On the other hand, in agreement with other previous observations, we have recently demonstrated the direct contribution of PLD activation in promoting intracellular mycobacterial killing. In this case, PLD inhibition resulted in a significant reduction of antimicrobial innate immune response and, hence, in a possible harmful effect. In the light of the above reported considerations, besides the recent advances in characterising new compounds able to selectively inhibit PLD activity and/or signalling, this review aimed at elucidating the potential dual beneficial/harmful consequences of PLD activity modulation.

AB - One of the most promising strategies for drug design and development is the identification of new molecules able to selectively inhibit those enzymes involved in pathological processes, without affecting other enzymes associated with physiological functions. Nevertheless, some enzymes can show a double-edge aspect of their own inhibition, which can lead to positive as well as negative consequences according to the pathological state. Phospholipase D (PLD), an ubiquitous enzyme nowadays considered as a critical regulator of several aspects of cell biology and signal transduction pathways, is a clear example of those double-dealer enzymes. While a great deal has been learned about PLD structure, biological functions and activation/regulation mechanisms, little yet is known about the derivable effects of its potential negative regulation, also due to the lack of specific inhibitors. Multiple evidences on PLD involvement in many pathological states development and progression, including inflammation, carcinogenesis and metastases, have been supplied, so that a deregulation of its activity could contribute to attenuate or slow down the inflammatory and tumour formation/progression processes. On the other hand, in agreement with other previous observations, we have recently demonstrated the direct contribution of PLD activation in promoting intracellular mycobacterial killing. In this case, PLD inhibition resulted in a significant reduction of antimicrobial innate immune response and, hence, in a possible harmful effect. In the light of the above reported considerations, besides the recent advances in characterising new compounds able to selectively inhibit PLD activity and/or signalling, this review aimed at elucidating the potential dual beneficial/harmful consequences of PLD activity modulation.

KW - Inflammation

KW - Inhibition

KW - Oxidative burst

KW - Phagocytosis

KW - Phospholipase D

KW - Tuberculosis

KW - Tumour

UR - http://www.scopus.com/inward/record.url?scp=36949023087&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36949023087&partnerID=8YFLogxK

U2 - 10.2174/157340807782330255

DO - 10.2174/157340807782330255

M3 - Article

VL - 3

SP - 309

EP - 333

JO - Current Enzyme Inhibition

JF - Current Enzyme Inhibition

SN - 1573-4080

IS - 4

ER -