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J Biol Chem, Vol. 274, Issue 42, 29786-29790, October 15, 1999
From the Department of Biological Sciences, St. John's University, Jamaica, New York 11439
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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The topography of formation and migration of
phosphatidic acid (PA) in the transverse plane of rat liver
mitochondrial outer membrane (MOM) were investigated. Isolated
mitochondria and microsomes, incubated with sn-glycerol
3-phosphate and an immobilized substrate palmitoyl-CoA-agarose,
synthesized both lyso-PA and PA. The mitochondrial and microsomal
acylation of glycerophosphate with palmitoyl-CoA-agarose was 80-100%
of the values obtained in the presence of free palmitoyl-CoA. In
another series of experiments, both free polymyxin B and polymyxin B-agarose stimulated mitochondrial glycerophosphate acyltransferase activity approximately 2-fold. When PA loaded mitochondria were treated
with liver fatty acid binding protein, a fifth of the phospholipid left
the mitochondria. The amount of exportable PA reduced with the increase
in the time of incubation. In another approach, PA-loaded mitochondria
were treated with phospholipase A2. The amount of
phospholipase A2-sensitive PA reduced when the incubation
time was increased. Taken together, the results suggest that
lysophosphatidic acid (LPA) and PA are synthesized on the outer surface
of the MOM and that PA moves to the inner membrane presumably for
cardiolipin formation.
Phosphatidic acid (PA),1
the key intermediate in the biosynthetic pathway of glycerolipids, is
synthesized by two successive acylations of glycerol 3-phosphate (1).
The acylation steps are carried out by glycerophosphate acyltransferase
(GAT) (2) and monoacylglycerolphosphate acyltransferase (MGAT) (3). In mammalian cells, these enzymes are located in both MOM and endoplasmic reticulum (4-6). A substantial amount of knowledge has accumulated on
mitochondrial GAT regarding its properties (7, 8), purification (9,
10), and cloning (11, 12). On the other hand, very little is known
about MGAT.
Several lines of evidence suggest that the mitochondrial GAT regulates
the selective positioning of saturated fatty acids at the
sn-1 position of glycerophospholipids. The selective
positioning of the fatty acids is considered to be important in the
structural and functional role of biological membranes (13, 14). Unlike the microsomal GAT, the mitochondrial enzyme has strong preference for
saturated fatty acyl-CoAs as substrate (4, 5). In Ehrlich ascites tumor
cells (15) and in primary tissue culture cells (16), the mitochondrial
acyltransferase activity is inversely proportional to the randomization
of fatty acids at position 1. Finally, lysophosphatidic acid (LPA),
synthesized in mitochondria, can exit the organelle, be transported to
the endoplasmic reticulum in the presence of liver fatty acid binding
protein (L-FABP), and be converted to PA (17). Recent
experiments from different laboratories also suggest that the activity
of mitochondrial GAT can change under different physiological (18, 19)
and nutritional conditions (20, 21) and in the presence of some
metabolic modulators (22). These observations suggest that
mitochondrial GAT can be controlled at the level of transcription as
well as by modulators of activity.
Biochemical investigations using proteases suggest that the rat
mitochondrial GAT is a transmembrane protein (23). Cloning and
sequencing of the cDNA (GenBankTM accession number
U36771) revealed the presence of two transmembrane regions (12),
supporting the biochemical observation.
Our previous work suggests that acyl-CoA synthetase, which activates
fatty acids, spans the MOM (24). By using desulfo-CoA-agarose, an
immobilized competitive inhibitor, we established that the catalytic
site of the enzyme is located in the outer aspect of the MOM. The
acyl-CoA formed can be used either catabolically for This paper deals with the location of synthesis of LPA and PA in the
transverse plane of the MOM and the extent of translocation of PA
necessary for cardiolipin synthesis. Our result suggests that both LPA
and PA are synthesized on the outer aspect of the MOM, and
subsequently, PA moves to the inner membrane as a precursor of cardiolipin.
Materials--
Male Harlan Sprague-Dawley rats were purchased
from Taconic Farms, Germantown, NY.
sn-[2-3H]Glycerol 3-phosphate (1.11 × 104 cpm/nmol) was obtained from American Radiochemicals
Inc. Palmitoyl-CoA-agarose, and polymyxin B-agarose, obtained from
Sigma, were washed four times with 40 mM MTG buffer
(MES/TES/glycylglycine), pH 7.5, before use. All other materials were
obtained as described previously (23).
Preparation of Mitochondria and Microsome--
Liver
mitochondria and microsome were prepared from 175-200-g male Harlan
Sprague-Dawley rats as described previously (4). The purity of both
preparations was evaluated by performing GAT assay in the presence and
absence of 2 mM N-ethylmaleimide, which is an
inhibitor of the microsomal GAT (15). Cross-contamination between
mitochondrial and microsomal fractions was <3%.
Analytical Methods--
GAT activity was measured by following
the incorporation of sn-[2-3H]glycerol
3-phosphate into butanol-extractable phospholipids (15). Asolectin was
omitted from the system. The concentration of the subcellular protein
in the incubation medium was maintained between 0.2 and 0.4 mg/ml. For
sedimenting mitochondria or microsomes, the incubated mixture was
cooled to 0 °C and spun at 10,000 × g for 15 min or
at 105,000 × g for 60 min, respectively. The pellet was resuspended in 0.5 ml of water. The supernatant, the resuspended pellet, or whole GAT reaction mixture was treated with 1-butanol to
extract the radioactive acylation products, LPA and PA, which were
separated by thin layer (4) or high performance thin layer chromatography. Protein concentration was assayed as per the Bradford method (25) using bovine serum albumin as a standard.
Activity of Mitochondrial and Microsomal GAT Using
Palmitoyl-CoA-Agarose as Acyl Donor--
Palmitoyl-CoA is commercially
available cross-linked to 4% beaded agarose. As the linkage of agarose
is with the amino group of CoA with a 7-carbon spacer, it is not
possible that the activated acyl group can cross the MOM phospholipid
bilayer and reach the inner aspect of the membrane. Microsomal GAT has
its catalytic site on the outer surface of the membrane (7) and was
used as a positive control. Fig. 1
documents the activity of mitochondrial and microsomal GAT at different
concentrations of palmitoyl-CoA and palmitoyl-CoA-agarose. For both
mitochondria and microsomes, their activities of GAT is over 90% in
the presence of immobilized substrate when compared with the activities
in presence of free palmitoyl-CoA. Since the concentration of
palmitoyl-CoA in the immobilized sample cannot be accurately measured,
comparison can be made between the activities in the presence of free
and bound palmitoyl-CoA at their optimal level of activity.
The palmitoyl-CoA-agarose was washed four times before use. There was
virtually no difference in the GAT activity using washed or unwashed
samples suggesting that the beads contained no free palmitoyl-CoA. To
determine whether free palmitoyl-CoA was released during the assay, we
measured the incorporation of glycerophosphate into phospholipids at 1, 2, and 3 min of incubation with optimal concentrations of free and
immobilized substrate. In both instances, the rate of incorporation was
linear with time (results not shown). Therefore, the acyl-CoA was
indeed immobilized and was not available to the inner side of the MOM.
The activity of GAT in the presence of palmitoyl-CoA-agarose was not a
reflection of disruption of mitochondria. The latency of cytochrome
oxidase of this and similarly prepared samples revealed only 10-15%
disruption of mitochondria.
The Effect of Immobilized Polymyxin B-Agarose on Mitochondrial and
Microsomal Glycerophosphate Acyltransferase--
It is known that
polymyxin B stimulates the mitochondrial GAT and markedly inhibits the
microsomal enzyme (Refs. 26-28, Fig. 2A). In the presence of
polymyxin B-agarose, mitochondria and microsomes showed activation and
inhibition in the range of 80-90% of the values obtained in the
presence of free polymyxin B (Fig. 2C). The immobilized
polymyxin B is cross-linked to 4% beaded agarose through an amino
group with a spacer of 1 carbon. It is, therefore, improbable that the
antibiotic can penetrate the MOM. Fig. 2 also includes the results
using palmitoyl-CoA-agarose and polymyxin B (Fig. 2B) and
palmitoyl-CoA-agarose and polymyxin B-agarose (Fig. 2D).
Both the free and immobilized polymyxin B stimulated the mitochondrial
and inhibited the microsomal GAT. For reason presently unknown,
polymyxin B-agarose, at higher concentrations, is less effective in
both stimulating and inhibiting mitochondrial and microsomal GAT,
respectively (Fig. 2, C and D).
Acylation Products Formed in the Presence of Immobilized
Substrate--
Amounts of LPA and PA synthesized in mitochondria and
microsomes using palmitoyl-CoA and palmitoyl-CoA-agarose as acyl donor are documented in Fig. 3. Both the
phospholipids were formed in equal quantities in presence of free
palmitoyl-CoA in mitochondria (15). In microsomes, the amount of LPA
was about 30%. A similar profile was seen with the use of
palmitoyl-CoA-agarose. In the absence of bovine serum albumin, mainly
PA was formed in both microsomes and mitochondria.
Role of L-FABP in the Export of Mitochondrial LPA and PA--
As
reported earlier (17), L-FABP stimulates the export of LPA
from mitochondria. The presence of L-FABP stimulates LPA
synthesis 6-fold but reduced PA synthesis by 50%. In the absence of
L-FABP, mitochondria can synthesize significant amount of
PA, which remains in the mitochondria. However, this PA was marginally
exported when mitochondria were exposed to L-FABP (Fig.
4). When mitochondria, loaded with PA,
were immediately exposed to 35 µM L-FABP, up
to 21% of PA left the mitochondria. The amount of PA available for export decreased with time, suggesting that the PA became inaccessible for binding to L-FABP.
Preferential export of LPA from mitochondria due to L-FABP
is documented in Fig. 5. Mitochondria,
loaded with PA, were treated with liver cytosol, which resulted in
partial conversion of PA to LPA and glycerides. Subsequent exposure of
these mitochondria to L-FABP resulted in 94% release of
LPA but only 22% release of PA and 6% release of glycerides. Data
shown in Fig. 4 suggest that, with time, PA within mitochondria is
becoming less available for export. This observation was confirmed by
another approach. Mitochondria, loaded with PA, were exposed either to
phospholipase A2 alone or to a mixture of phospholipase
A2 and L-FABP. LPA, generated by phospholipase
A2 from PA, was exported 2.5-fold more efficiently in the
presence of L-FABP and phospholipase A2 than in
the presence of phospholipase A2 only (Fig.
6). When PA-loaded mitochondria were
incubated for 30 min in buffer A prior to phospholipase A2
and L-FABP, the amount of exported LPA was reduced to 30%. However, mitochondria after 30-min incubation contained 85-95% of
originally present PA. Thus, breakdown of PA was not responsible for
reduction in PA release.
Two main points emerge from this investigation. First, both LPA
and PA are synthesized on the cytosolic side of the MOM. Second, the PA
synthesized rapidly moves from the outer surface, presumably to the
inner membrane where it is converted to cardiolipin (29). In the
presence of the immobilized substrate palmitoyl-CoA-agarose, the GAT
activity of isolated mitochondria was about the same as that in the
presence of the free acyl-CoA (Fig. 1), suggesting that the outer
surface of the MOM is the site of LPA formation. This conclusion is in
keeping with the results obtained by the use of the immobilized
stimulator of the mitochondrial GAT, polymyxin B-agarose. Since
mitochondrial GAT could be stimulated approximately 2-fold in the
presence of either free or immobilized polymyxin B (Fig. 2), it is
suggestive that the catalytic site of mitochondrial GAT is exposed
to the cytosolic side of the MOM.
If LPA is formed on the outer surface of the MOM, which side of the
membrane is PA formed? Analysis of the acylation products (Fig. 3)
revealed that both LPA and PA were formed in the presence of the free
or agarose-bound palmitoyl-CoA. Absence of bovine serum albumin in the
incubation medium similarly affected the LPA:PA ratio with the two
forms of the acyl-CoA. As expected (15), in the absence of bovine serum
albumin, PA was the main reaction product. These results strongly
suggest that both LPA and PA are made on the outer side of the MOM.
Formation of both the phospholipids is stimulated in the presence of
free or agarose-bound polymyxin B (results not shown), further
confirming the site of formation of the phospholipids in the transverse
plane of the MOM.
The results obtained here, together with those reported earlier on the
formation acyl-CoA on the cytosolic side of the MOM (24), indicate that
the three enzymes, acyl-CoA synthetase, GAT, and MGAT, all can draw on
the cytosolic pool of substrates. This situation raises the possibility
that these three enzymes are closely located and that there could be an
efficient substrate "channeling" between these enzymes.
The PA synthesized on the outer surface of the MOM leaves the organelle
to a very limited extent (Figs. 4 and 6). It can be converted to
diacylglycerol by phosphatidate phosphohydrolase (30) or can be
converted back to LPA under certain conditions by phospholipase
A2, which is also located in the MOM (31, 32). The fate of
the mitochondrially synthesized PA is its conversion to cardiolipin,
the final step of which takes place in the inner membrane (33, 34).
There is precursor-product relationship between PA and cardiolipin when
PA-loaded mitochondria are incubated in a cardiolipin-synthesizing
medium. Furthermore, the final step of cardiolipin synthesis takes
place on the inner side of the inner membrane (29). Thus, there is a
complex topological movement of PA from the outer surface of the outer
membrane to the inner surface of the inner membrane. Transport of PA
from the outer to inner membrane may occur either by simple diffusion
(35) or by some other mechanism, for example, involving some
transport protein. However, the movement of PA from the outer
to inner membrane fits in with our observation that incubation of
PA-loaded mitochondria renders the phospholipid inaccessible to
externally added phospholipase A2 (Fig. 6).
It appears that each of the products of the three enzymes, acyl-CoA
synthetase, GAT, and MGAT, has at least two possible fates (Fig.
7). The acyl-CoA synthesized in the
mitochondria can either be transported to the mitochondrial matrix for
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
-oxidation of
the fatty acids in the mitochondrial matrix or can be used anabolically
to acylate glycerophosphate. The synthesis of acyl-CoA on the outer
surface of the MOM leads to the question: which leaflet of the MOM is
involved in the synthesis of LPA and PA?
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
View larger version (13K):
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Fig. 1.
Comparison of the optimal activity of
mitochondrial ( 
) and microsomal (
) GAT using palmitoyl-CoA
(A) and palmitoyl-CoA-agarose (B) as
acyl donor. The reaction was initiated by the addition of the
subcellular fraction. The final protein concentration was adjusted to
0.2 mg/ml for both mitochondria and microsomes. The values are the
average of two separate sets of experiments.
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Fig. 2.
Differential action of polymyxin B and
polymyxin B-agarose on mitochondrial ( ) and microsomal ()
GAT. The assays were performed at the optimal concentrations of
palmitoyl-CoA and palmitoyl-CoA-agarose for the subcellular fractions.
Different concentrations of free and immobilized polymyxin B were added
to the assay medium. The reaction was initiated by the addition of the
subcellular fraction. A and C contain results
obtained with palmitoyl-CoA, whereas B and D contain results obtained
with palmitoyl-CoA-agarose. The mitochondrial and microsomal GAT
activities in the absence of polymyxin B were 2-3 and 3-4
nmol/min/mg, respectively. The values in the figure are the average of
two separate sets of experiments.
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Fig. 3.
Acylation products formed in the presence of
palmitoyl-CoA-agarose. Mitochondria (0.64 mg/ml) and microsomes
(1.76 mg/ml) were incubated in the GAT assay medium in a total volume
of 0.5 ml. The formation of LPA ( 
) and PA (
) was analyzed by thin
layer chromatography. The values in the figure are the average of four
separate sets of experiments.
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Fig. 4.
Export of PA from mitochondria.
Mitochondria (0.4-0.6 mg/ml) were incubated in GAT assay medium for 10 min and then diluted five times with ice-cold buffer A (0.25 M sucrose, 10 mM Tris, 2 mM EDTA,
pH 7.4) and pelleted by centrifugation at 4 °C, 10,000 × g for 15 min. The sediment was resuspended in buffer B (20 mM Tris, 10% glycerol, 2 mM EDTA, pH 7.4) and
divided in 0.5-ml aliquots. Each aliquot contained 1.42 nmol of PA,
0.42 nmol of glycerides (mono and diacyl), and 0.37 mg of mitochondrial
protein. Mitochondria were incubated with shaking for 0, 20, and 40 min
at 25 °C and then L-FABP was added at indicated
concentrations, and the volume was made up with buffer A to 1 ml. After
5 min, the mitochondria were pelleted by centrifugation at 10,000 × g for 10 min. The supernatant was treated with 1-butanol
and PA, and glycerides were separated by thin layer chromatography.
Results are presented as PA ( 
, , 
) or glycerides (
)
released after 0-min (), 2 (), 20-min (), or 40-min ()
incubation of mitochondria prior to L-FABP addition.
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Fig. 5.
Release of LPA, PA, and glycerides from
mitochondria. Mitochondria were loaded with PA and resuspended in
buffer B (20 mM Tris/HCl buffer, pH 7.4, 10% glycerol, 5 mM CaCl2) to 3 mg/ml mitochondrial protein.
Crude liver cytosol was added (1 mg/ml), and the incubation was
continued for 10 min at 25 °C. The mitochondria were spun down,
reconstituted in buffer A, and divided into 0.5-ml aliquots. Each
aliquot contained 0.38 nmol of LPA, 0.41 nmol of PA, 0.68 nmol of
glycerides, and 0.62 mg of mitochondrial protein. L-FABP
was added at indicated concentrations, and the volume was made up with
buffer A to 1 ml. After 5 min, the mitochondria were pelleted by
centrifugation. The supernatant was extracted with 1-butanol and LPA
( 
), PA (), and glycerides () separated by thin layer
chromatography. Results are present as the amount released from one
aliquot (0.62 mg of mitochondrial protein).
View larger version (12K):
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Fig. 6.
Phospholipase A2 sensitivity of
mitochondrial PA. Mitochondria were loaded with PA, pelleted by
centrifugation, resuspended in buffer B, and divided in 0.5-ml
aliquots. Each aliquot contained 1.56 nmol of PA, 0.36 nmol of
glycerides, and 0.44 mg of mitochondrial protein. Phospholipase
A2 (5 µg/ml; , ) or mixture of phospholipase
A2 (5 µg/ml) and L-FABP (35 µM)(
, ) were added either immediately (, ),
or PA-loaded mitochondria were incubated for 30 min at 25 °C prior
to addition of these proteins (, ). The mitochondria were
pelleted and processed as described in the legend to Fig. 5. Results
are presented as the amount released from one aliquot (0.44 mg of
mitochondrial protein).
DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
-oxidation or be acted upon by GAT to form LPA. It is known that
fatty acid biosynthesis is regulated by metabolic modulators (36).
Similarly, as GAT is influenced by ATP and citrate (22), they can very well be involved in this regulation. Similar to acyl-CoA, the LPA
formed in the MOM has also two fates. It can either be acylated to form
PA (6), or it can combine with L-FABP and be exported to
the endoplasmic reticulum for conversion to PA (17, 37) and presumably
to other phospholipids. LPA-FABP does not act as a substrate for
mitochondrial MGAT (17). A small amount of PA can leave the
mitochondria. Whether this PA is transported to the endoplasmic
reticulum for conversion to complex phospholipids is unknown. However,
the majority of mitochondrially synthesized PA appears to be converted
to cardiolipin. The dual fate of acyl-CoA, LPA, and PA suggest the
existence of multiple control sites in the metabolism of these
compounds.
View larger version (32K):
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Fig. 7.
Illustration showing the interplay of
mitochondria and endoplasmic reticulum (microsomes) in determining
possible fates of fatty acyl-CoA, LPA, and PA. *, used in
-oxidation.
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ACKNOWLEDGEMENT |
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We thank Shaista Hussain for her help during the course of this work.
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FOOTNOTES |
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* This work was supported by National Institutes of Health Grant GM-57643.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 718-990-1697;
Fax: 718-990-5958; E-mail: haldard@stjohns.edu.
¶ This paper is dedicated to the loving memory of Professor Naba K. Gupta, University of Nebraska, Lincoln, NE. He was not only a superior scientist, but also a warm-hearted human being.
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ABBREVIATIONS |
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The abbreviations used are: PA, phosphatidic acid; LPA, lysophosphatidic acid; MOM, mitochondrial outer membrane; GAT, glycerophosphate acyltransferase; MGAT, monoacylglycerolphosphate acyltransferase; L-FABP, liver fatty acid-binding protein; MES, 4-morpholineethanesulfonic acid; TES, N-tris(hydroxymethyl)methyl-2- aminoethanesulfonic acid.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
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  S. E. Gale, A. Frolov, X. Han, P. E. Bickel, L. Cao, A. Bowcock, J. E. Schaffer, and D. S. Ory A Regulatory Role for 1-Acylglycerol-3-phosphate-O-acyltransferase 2 in Adipocyte Differentiation J. Biol. Chem., April 21, 2006; 281(16): 11082 - 11089. [Abstract] [Full Text] [PDF]
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 M. Bektas, S. G. Payne, H. Liu, S. Goparaju, S. Milstien, and S. Spiegel A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells J. Cell Biol., June 6, 2005; 169(5): 801 - 811. [Abstract] [Full Text] [PDF]
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 M. Coon, A. Ball, J. Pound, S. Ap, D. Hollenback, T. White, J. Tulinsky, L. Bonham, D. K. Morrison, R. Finney, et al. Inhibition of lysophosphatidic acid acyltransferase {beta} disrupts proliferative and survival signals in normal cells and induces apoptosis of tumor cells Mol. Cancer Ther., October 1, 2003; 2(10): 1067 - 1078. [Abstract] [Full Text]
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 D. R. Voelker New perspectives on the regulation of intermembrane glycerophospholipid traffic J. Lipid Res., March 1, 2003; 44(3): 441 - 449. [Abstract] [Full Text] [PDF]
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F. Y. Xu, W. A. Taylor, J. A. Hurd, and G. M. Hatch Etomoxir mediates differential metabolic channeling of fatty acid and glycerol precursors into cardiolipin in H9c2 cells J. Lipid Res., February 1, 2003; 44(2): 415 - 423. [Abstract] [Full Text] [PDF]
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M. R. Gonzalez-Baro, D. A. Granger, and R. A. Coleman Mitochondrial Glycerol Phosphate Acyltransferase Contains Two Transmembrane Domains with the Active Site in the N-terminal Domain Facing the Cytosol J. Biol. Chem., November 9, 2001; 276(46): 43182 - 43188. [Abstract] [Full Text] [PDF]
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 M. D. Esposti, J. T. Erler, J. A. Hickman, and C. Dive Bid, a Widely Expressed Proapoptotic Protein of the Bcl-2 Family, Displays Lipid Transfer Activity Mol. Cell. Biol., November 1, 2001; 21(21): 7268 - 7276. [Abstract] [Full Text] [PDF]
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V. S. Balija, T. R. Chakraborty, A. V. Nikonov, T. Morimoto, and D. Haldar Identification of Two Transmembrane Regions and a Cytosolic Domain of Rat Mitochondrial Glycerophosphate Acyltransferase J. Biol. Chem., October 6, 2000; 275(41): 31668 - 31673. [Abstract] [Full Text] [PDF]
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