Phospholipase D (PLD) is an enzyme that hydrolyzes glycerophospholipids, leading to the production of phosphatidic acid and a free headgroup. The enzyme's structure is characterized by regulatory sequences and conserved regions that are crucial for its catalytic activity, which can occur in different modes of interfacial catalysis. PLD is regulated by cell surface receptors and intracellular signals and presents therapeutic opportunities for inhibition.

1. Phospholipase D: An Interfacial
Enzyme of Lipid Metabolism
SAKEEL AHMED (PhD Scholar)
Department of Pharmacology (NIPER, Mohali)

2.  Phospholipase D catalyzes the hydrolysis of the phosphodiester bond of glycerophospholipids to generate
phosphatidic acid and a free headgroup.
 Phospholipase D (PLD) activity was first discovered in carrot extracts as a phospholipid-specific
phosphodiesterase activity that hydrolysed phosphatidylcholine to yield phosphatidic acid (PA) and choline
Phospholipase D (PLD)

3. Structure of Phospholipase D
Catalytic domain is flanked by regulatory sequences. These include lipid-binding PX and
PH domains, as well as motifs that are unique to the PLD enzymes
The catalytic core of the eukaryotic PLD enzymes consists of four conserved regions (I–
IV).
Domains II and IV are particularly highly conserved and contain the invariant charged
motif, HxKxxxxD (HKD).

4. Mechanism of PLD Activity
Figure. Mechanisms of phospholipase D enzyme activities.

5. FIG. Schematic illustration of the two
extreme modes of interfacial catalysis on
vesicles. In the scooting mode (top) the
enzyme bound to the interface does not
dissociate during several thousand
turnover cycles. Under these conditions
the bound enzyme "sees“ only the
substrate and inhibitor at the interface to
which it is bound, and the excess vesicles
which do not contain enzyme are not
hydrolyzed, In the hopping mode (bottom)
the enzyme desorbs from the interface
after each or a few turnover cycles. Thus
excess vesicles are ultimately accessible
for hydrolysis.

6. Fig. PLD-catalyzed hydrolysis and transphosphatidylation
reactions.

7. Regulation of PLD
Fig. Regulation of PLD by cell surface receptors and intracellular signals through actions of intermediate
protein and lipid activators.

8. Biological Importance of PLD
Figure. Therapeutic opportunities for PLD
inhibition.

9. References
 Selvy, P. E., Lavieri, R. R., Lindsley, C. W. & Brown, H. A. Phospholipase D : Enzymology
, Functionality , and Chemical Modulation. 6064–6119 (2011).
 Majd, S., Yusko, E. C., Yang, J., Sept, D. & Mayer, M. A Model for the Interfacial
Kinetics of Phospholipase D Activity on Long- Chain Lipids. Biophysj 105, 146–153
(2013).
 Mcdermott, M., Wakelam, M. J. O. & Morris, A. J. REVIEW / SYNTHÈSE Phospholipase
D 1 , 2. 253, 225–253 (2004).
 Freyberg, Z., Siddhanta, A. & Shields, D. ‘ Slip , sliding away ’: phospholipase D and the
Golgi apparatus. (2003)