cido fosfatdico

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Estructura de un fosfoglicrido; X representa el alcohol o aminoalcohol que se esterifica
con el grupo fosfato; el resto representa el cido fosfatdico.
El cido fosfatdico es un lpido compuesto por un glicerol con sus tres grupos hidroxilo
esterificados, dos de ellos por cidos grasos (uno saturado y otro insaturado) y el tercero
por un grupo fosfato. El grupo fosfato se esterifica a su vez con un alcohol o un
aminoalcohol (X en la figura).
El cido fosfatdico es la molcula a partir de la cual se forman los fosfoglicridos, un tipo
de fosfolpidos que forman la arquitectura bsica de las bicapas lipdicas de las membranas
celulares. Segn el alcohol unido al grupo fosfato se obtienen diferentes fosfoglicridos:
fosfatidilcolina (cido fosfatdico + colina), fosfatidilinositol (cido fosfatdico + inositol),
fosfatidiletanolamina (cido fosfatdico + etanolamina), fosfatidilserina (cido fosfatdico +
serina), etc.
El cido fosfatdico es tambin el punto de partida para la sntesis de triacilgliceroles
(triglicridos).
Biosntesis[editar]
El punto de partida de la ruta principal de sntesis del cido fosfatdico es el -glicerol 3-
fosfato, el cual proviene de la dihidroxiacetona fosfato, un intermediario de la gluclisis,
reaccin catalizada por la enzima glicerol-3-fosfato deshidrogenasa:

Otra va ms minoritaria de obtencin de glicerol 3-fosfato es por fosforilacin de glicerol
libre, gracias a la accin de la glicerol quinasa y el consumo de un ATP.
1

La sntesis de cido fosfatdico implica dos pasos con adicin secuencial de dos cidos
grasos en los hidroxilos 1 y 2 del glierol 3-fosfato, reacciones catalizadas por las
aciltransferasas I y II; los cidos grasos son aportados por acil CoA grasos:


























Phosphatidic acid
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Phosphatidic acids (PAs) are the acid forms of phosphatidates, a part of common
phospholipids, major constituents of cell membranes. Phosphatidic acids are the simplest
diacyl-glycerophospholipids.
[1]

Contents
[hide]
1 Structure
2 Formation and degradation
3 The role of PA in the cell
4 PA as a biosynthetic precursor
5 Biophysical properties of PA
6 Measurement of PA production
7 PA as a signalling lipid
8 Proteins known to interact with PA
9 References
10 External links
Structure[edit]


General chemical structure of phosphatidic acids
Phosphatidic acid consists of a glycerol backbone, with, in general, a saturated fatty acid
bonded to carbon-1, an unsaturated fatty acid bonded to carbon-2, and a phosphate group
bonded to carbon-3.
[1][2]

Formation and degradation[edit]
Besides de novo synthesis, PA can be formed in three ways:
By phospholipase D (PLD), via the hydrolysis of the P-O bond of phosphatidylcholine (PC)
to produce PA and choline.
[3]

By the phosphorylation of diacylglycerol (DAG) by DAG kinase (DAGK)
By the acylation of lysophosphatidic acid by lysoPA-acyltransferase (LPAAT); this is the
most common pathway.
[4]


PA is degraded by conversion into DAG by lipid phosphate phosphohydrolases (LPPs)
[5][6]

or into lyso-PA by phospholipase A (PLA).
The role of PA in the cell[edit]
The role of PA in the cell can be divided into three categories:
PA is the precursor for the biosynthesis of many other lipids.
The physical properties of PA influence membrane curvature.
PA acts as a signaling lipid, recruiting cytosolic proteins to appropriate membranes (e.g.,
sphingosine kinase 1
[7]
).
PA plays very important role in Phototransduction in Drosophila
[8]

The first three roles are not mutually exclusive. For example, PA may be involved in
vesicle formation by promoting membrane curvature and by recruiting the proteins to carry
out the much more energetically unfavourable task of neck formation and pinching.
PA as a biosynthetic precursor[edit]
PA is a vital cell lipid that acts as a biosynthetic precursor for the formation (directly or
indirectly) of all acylglycerol lipids in the cell.
[9]

In mammalian and yeast cells, two different pathways are known for the de novo synthesis
of PA, the glycerol 3-phosphate pathway or the dihydroxyacetone phosphate pathway. In
bacteria, only the former pathway is present, and mutations that block this pathway are
lethal, demonstrating the importance of PA. In mammalian and yeast cells, where the
enzymes in these pathways are redundant, mutation of any one enzyme is not lethal.
However, it is worth noting that in vitro, the various acyltransferases exhibit different
substrate specificities with respect to the acyl-CoAs that are incorporated into PA. Different
acyltransferases also have different intracellular distributions, such as the endoplasmic
reticulum (ER), the mitochondria or peroxisomes, and local concentrations of activated
fatty acids. This suggests that the various acyltransferases present in mammalian and yeast
cells may be responsible for producing different pools of PA.
[9]

The conversion of PA into diacylglycerol (DAG) by LPPs is the commitment step for the
production of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and
phosphatidylserine (PS). In addition, DAG is also converted into CDP-DAG, which is a
precursor for phosphatidylglycerol (PG), phosphatidylinositol (PI) and phosphoinositides
(PIP, PIP
2
, PIP
3
).
[9]

PA concentrations are maintained at extremely low levels in the cell by the activity of
potent LPPs.
[5]
These convert PA into DAG very rapidly and, because DAG is the precursor
for so many other lipids, it too is soon metabolised into other membrane lipids. This means
that any upregulation in PA production can be matched, over time, with a corresponding
upregulation in LPPs and in DAG metabolising enzymes.
PA is, therefore, essential for lipid synthesis and cell survival, yet, under normal conditions,
is maintained at very low levels in the cell.
Biophysical properties of PA[edit]
PA is a unique phospholipid in that it has a small highly-charged head group that is very
close to the glycerol backbone. PA is known to play roles in both vesicle fission
[10]
and
fusion,
[11]
and these roles may relate to the biophysical properties of PA.
At sites of membrane budding or fusion, the membrane becomes or is highly curved. A
major event in the budding of vesicles, such as transport carriers from the Golgi, is the
creation and subsequent narrowing of the membrane neck. Studies have suggested that this
process may be lipid-driven, and have postulated a central role for DAG due to its,
likewise, unique molecular shape. The presence of two acyl chains but no headgroup results
in a large negative curvature in membranes.
[12]

The LPAAT BARS-50 has also been implicated in budding from the Golgi.
[10]
This
suggests that the conversion of lysoPA into PA might affect membrane curvature. LPAAT
activity doubles the number of acyl chains, greatly increasing the cross-sectional area of the
lipid that lies within the membrane while the surface headgroup remains unchanged. This
can result in a more negative membrane curvature. Researchers from Utrecht University
have looked at the effect of lysoPA versus PA on membrane curvature by measuring the
effect these have on the transition temperature of PE from lipid bilayers to nonlamellar
phases using
31
P-NMR.
[13]
The curvature induced by these lipids was shown to be
dependent not only on the structure of lysoPA versus PA but also on dynamic properties,
such as the hydration of head groups and inter- and intramolecular interactions. For
instance, Ca
2+
may interact with two PAs to form a neutral but highly-curved complex. The
neutralisation of the otherwise repulsive charges of the headgroups and the absence of any
steric hindrance enables strong intermolecular interactions between the acyl chains,
resulting in PA-rich microdomains. Thus in vitro, physiological changes in pH,
temperature, and cation concentrations have strong effects on the membrane curvature
induced by PA and lysoPA.
[13]
The interconversion of lysoPA, PA, and DAG - and changes
in pH and cation concentration - can cause membrane bending and destabilisation, playing
a direct role in membrane fission simply by virtue of their biophysical properties. However,
though PA and lysoPA have been shown to affect membrane curvature in vitro; their role in
vivo is unclear.
The roles of lysoPA, PA, and DAG in promoting membrane curvature do not preclude a
role in recruiting proteins to the membrane. For instance, the Ca
2+
requirement for the
fusion of complex liposomes is not greatly affected by the addition of annexin I, though it
is reduced by PLD. However, with annexin I and PLD, the extent of fusion is greatly
enhanced, and the Ca
2+
requirement is reduced almost 1000-fold to near physiological
levels.
[11]

Thus the metabolic, biophysical, recruitment, and signaling roles of PA may be interrelated.
Measurement of PA production[edit]
As PA is rapidly converted to DAG, it is very short-lived in the cell. This means that it is
difficult to measure PA production and therefore to study the role of PA in the cell.
However, PLD activity can be measured by the addition of primary alcohols to the cell.
[14]

PLD then carries out a transphosphatidylation reaction, instead of hydrolysis, producing
phosphatidyl alcohols in place of PA. The phosphatidyl alcohols are metabolic dead-ends,
and can be readily extracted and measured. Thus PLD activity and PA production (if not
PA itself) can be measured, and, by blocking the formation of PA, the involvement of PA
in cellular processes can be inferred.
PA as a signalling lipid[edit]
As described above, PLD hydrolyzes PC to form PA and choline. Because choline is very
abundant in the cell, PLD activity does not significantly affect choline levels; and choline is
unlikely to play any role in signaling.
The role of PLD activation in numerous signaling contexts, combined with the lack of a
role for choline, suggests that PA is important in signaling. However, PA is rapidly
converted to DAG, and DAG is also known to be a signaling molecule. This raises the
question as to whether PA has any direct role in signaling or whether it simply acts as a
precursor for DAG production.
[15][16]
If it is found that PA acts only as a DAG precursor,
then one can raise the question as to why cells should produce DAG using two enzymes
when they contain the PLC that could produce DAG in a single step.
PA produced by PLD or by DAGK can be distinguished by the addition of [-
32
P]ATP.
This will show whether the phosphate group is newly derived from the kinase activity or
whether it originates from the PC.
[17]

Although PA and DAG are interconvertible, they do not act in the same pathways. Stimuli
that activate PLD do not activate enzymes downstream of DAG, and vice versa. For
example it was shown that addition of PLD to membranes results in the production of [
32
P]-
labeled PA and [
32
P]-labeled phosphoinositides.
[18]
The addition of DAGK inhibitors
eliminates the production of [
32
P]-labeled PA but not the PLD-stimulated production of
phosphoinositides.
It is possible that, though PA and DAG are interconvertible, separate pools of signaling and
non-signaling lipids may be maintained. Studies have suggested that DAG signaling is
mediated by polyunsaturated DAG, whereas PLD-derived PA is monounsaturated or
saturated. Thus functional saturated/monounsaturated PA can be degraded by hydrolysing it
to form non-functional saturated/monounsaturated DAG, whereas functional
polyunsaturated DAG can be degraded by converting it into non-functional polyunsaturated
PA.
[15][19]

This model suggests that PA and DAG effectors should be able to distinguish lipids with
the same headgroups but with differing acyl chains. Although some lipid-binding proteins
are able to insert themselves into membranes and could hypothetically recognise the type of
acyl chain or the resulting properties of the membrane, many lipid-binding proteins are
cytosolic and localise to the membrane by binding only the headgroups of lipids. Perhaps
the different acyl chains can affect the angle of the head-group in the membrane. If this is
the case, it suggests that a PA-binding domain must not only be able to bind PA specifically
but must also be able to identify those head-groups that are at the correct angle. Whatever
the mechanism is, such specificity is possible. It is seen in the pig testes DAGK that is
specific for polyunsaturated DAG
[20]
and in two rat hepatocyte LPPs that dephosphorylate
different PA species with different activities.
[21]
Moreover, the stimulation of SK1 activity
by PS in vitro was shown to vary greatly depending on whether dioleoyl (C18:1), distearoyl
(C18:0), or 1-stearoyl, 2-oleoyl species of PS were used.
[22]
Thus it seems that, though PA
and DAG are interconvertible, the different species of lipid can have different biological
activities; and this may enable the two lipids to maintain separate signaling pathways.
Proteins known to interact with PA[edit]
SK1
PDE4A1
Raf1
mTOR
PP1
SHP1
Spo20p
p47phox
PKC
PLC
PIP5K.