Biomedical Engineering Reference
In-Depth Information
O
-
O
O
OH
OP
O
H
H
OH
X
NAPE-PLD
PLC
Y
O
-
O
-
O
O
OP
O
OP
O
H
H
O
O
RO
HO
Abh4
OR
OH
NArPE
NAT
O
-
OP
O
H
2
N
O
RO
OR
FIGURE 19.9
Biosynthesis of anandamide. The precursor phospholipids (NArPE) is generated from phos-
phatidylethanolamine by a
N
-acyltransferase (NAT). It can then be hydrolyzed by a phospholipase C (PLC),
by
N
-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD), or by alpha-beta-hydrolase
4 (Abh4). Other acylethanolamides may be formed by the same enzymes. (R = fatty acids). The enzymes “X”
and “Y” are not well characterized yet.
This enzyme uses acyl groups (e.g., arachidonoyl) from the
Sn
-1 position of phosphatidylcho-
line as substrate in the acylation process, and it will use whatever fatty acid is present. Thus, a
number of
N
-acylphosphatidylethanolamines are always formed having different fatty acids in
the
N
-acyl position of which
N
-arachidonoyl is only a minor component and those with palm-
itic acid, stearic acid, or oleic acid are much more abundant. From this precursor phospholipid,
N
-acyl-phosphatidylethanolamine, a number of different enzyme-catalyzed pathways can result in
the generation of acylethanolamides including anandamide that usually amounts to less than 5%
of the acylethanolamides (Figure 19.9). Which pathway is most relevant for a particular tissue or a
particular physiological/pathophysiological setting is not known at present. The cellular localization
of anandamide formation is not known and several of the involved enzymes have not been cloned
yet. The different acylethanolamides have a number of more or less specii c biological activities,
e.g., palmitoylethanolamide is anti-inl ammatory and oleoylethanolamide has anorexic and neuro-
protective activity that may be mediated via the activation of a transcription factor PPARa, and/
or an orphan receptor GPR119. Other acylethanolamides do not bind to the cannabinoid receptors.
Anandamide is a partial agonist for the cannabinoid receptors but it can also activate vanilloid
receptor and several different ion channels, but it is uncertain to what degree it does this
in vivo
.
All acylethanolamides are degraded by a fatty acylethanolamide hydrolase (FAAH) and FAAH-
knock out mice have increased levels of ananadmide and other acylethanolamides and increased
pain threshold. Acylethanolamides can also be degraded by some other hydrolases. Endogenous
levels of anandamide and other acylethanolamides are low and can be increased several fold during
tissue injury. It has been suggested that there exists an anandamide transporter responsible for the
uptake of anandamide into cells before it is degraded by the FAAH enzyme that is located in the
