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PubMed1980

Specificity of lysophospholipase D.

The specificity of lysophospholipase D (1-alkyl-sn-glycero-3-phosphoethanolamine ethanolaminehydrolase, EC 3.1.4.39; also works on choline analogs) for 1-alkyl- and 1-acyl-linked substrates was examined using rat liver microsomes. The microsomes were treated with diisopropylphosphorofluoridate to inhibit the hydrolysis of acyl chains from the acyl-linked compounds (1-palmitoyl-sn-glycero-3-phosphocholine and 1-palmitoyl-sn-glycero-3-phosphoethanolamine) and were treated with p-bromophenacyl bromide to block acylation of the compounds tested. In the presence of the inhibitors, 1-alkyl-sn-glycero-3-phosphocholine and 1-alkyl-sn-glycero-3-phosphoethanolamine were hydrolyzed extensively by lysophospholipase D but the corresponding 1-acyl-linked analogs were only negligibly hydrolyzed. Lysophospholipase D therefore appears to be specific for the ether-linked compounds. 1-Alk-1-'-enyl-sn-glycero-3-phosphoethanolamine (lyso plasmalogen) was also tested as a substrate, but a plasmalogenase in the rat liver microsomes rapidly hydrolyzed the compound and we were unable to determine whether it is a substrate for lysophospholipase D. Alkyl-linked substrates containing long-chain acyl groups at the 2-position are not hydrolyzed by the enzymes. We tested 1-alkyl-2-acetoyl-sn-glycero-3-phosphocholine and 1-alkyl-2-acetoyl-sn-glycero-3-phosphoethanolamine to determine if the less bulky, more hydrophilic acetate group would permit hydrolysis by lysophospholipase D; the derivatives did not appear to be attacked, except after hydrolysis of the acetate group. However, in the absence of inhibitors, the acetate groups were rapidly hydrolyzed by microsomal preparations.

Animals↗
PubMed1987

The metabolism of lyso-platelet-activating factor (1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine) by a calcium-dependent lysophospholipase D in rabbit kidney medulla.

A Ca2+-dependent lysophospholipase D activity in microsomal preparations from the rabbit kidney medulla hydrolyzes the choline moiety from 1-O-[9,10-3H]hexadecyl-2-lyso-sn-glycero-3-phosphocholine (lyso-PAF) to form 1-O-[9,10-3H]hexadecyl-2-lyso-sn-glycero-3-P; the latter is subsequently dephosphorylated by a phosphohydrolase to 1-O-[9,10-3H]hexadecyl-sn-glycerol. Sodium vanadate, which is known to inhibit phosphohydrolases, reduces the proportion of hexadecylglycerol and increases the formation of hexadecyl-lysoglycerophosphate. Essentially no hydrolysis occurs when the sn-2 position of the hexadecyllysoGPC substrate contains an acyl moiety. The lysophospholipase D in rabbit kidney is of microsomal origin and has a broad pH optimum between 8.0 and 8.8, with the activity decreasing sharply from pH 7.6 to 7.2. Wykle et al. (Biochim. Biophys. Acta 619 (1980) 58-67) have previously demonstrated the existence of a microsomal lysophospholipase D (specific for ether lipid substrates) in rat tissues that requires Mg2+ and exhibits a pH optimum of 7.2; high activities of the Mg2+-dependent lysophospholipase D were found in liver and brain, but not in kidney. In contrast to the Mg2+-dependent lysophospholipase D in rat tissues, the renal enzyme from rabbits requires Ca2+ (5 mM), whereas Mg2+ (5 mM) exhibits little stimulatory action. Under optimal assay conditions (0.1 M Tris-HCl (pH 8.4)/5 mM CaCl2), lysophospholipase D in the rabbit kidney medulla has an activity of 2.7 nmol/min per mg protein compared to 0.9 nmol/min per mg protein for the lysophospholipase D in the rat kidney medulla (0.1 M Tris-HCl (pH 7.2)/5 mM MgCl2). The Ca2+-dependent lysophospholipase D is highest in the liver and kidney medulla from rabbits, but is very low in rat tissues; similar activities were found in male and female rabbits. Our data indicate that the divalent metal ion requirements for expression of maximum lysophospholipase D activities can differ markedly among animal species and also suggest the microsomal Ca2+-dependent lysophospholipase D is an important catabolic route for lyso-PAF metabolism in rabbit renomedullary tissue.

Animals↗
PubMed1999

Substrate specificity of lysophospholipase D which produces bioactive lysophosphatidic acids in rat plasma.

Previously we reported that lysophospholipase D in rat plasma hydrolyzes endogenous unsaturated lysophosphatidylcholines (LPCs) preferentially to saturated LPCs to lysophosphatidic acids with growth factor-like and hormone-like activities. In this study, we examined the possibility that association of LPCs with different proteins in rat plasma has an effect on the preference of lysophospholipase D for unsaturated LPCs. Large portions of various LPCs were found to be recovered in the lipoprotein-poor bottom fraction. Furthermore, the percentages of LPCs associated with albumin isolated from rat plasma were shown not to be consistent with their percentage conversions to lysophosphatidic acids by lysophospholipase D on incubation of rat plasma at 37 degrees C. These results indicate that distinct distributions of LPCs in the plasma protein fractions are not critical factors for the substrate specificity of lysophospholipase D. Experiments with Nagase analbuminemic rats suggested that albumin-LPC complexes are not necessarily required for the hydrolysis by lysophospholipase D; lipoprotein-associate LPCs appeared to be good substrates for the phospholipase. We found that both saturated and unsaturated LPCs are present mainly as 1-acyl isomers in rat plasma. This result indicates that the preference of lysophospholipase D for unsaturated LPCs is not attributable to a difference in position of the acyl group attached to the glycerol backbone of LPC. In addition, lysophospholipase D was also found to attack choline phospholipids with a long chain group and a short chain alkyl group, although their percentage hydrolyses were low. Taken altogether, these results suggest that lysophospholipase D shows higher affinities for free forms of unsaturated acyl type LPCs equilibrated with albumin-bound and lipoprotein-associated forms, than for free forms of saturated acyl type LPCs and analogs of platelet-activating factor.

Animals↗
PubMed2006

Purification and characterization of lysophospholipase D from rat brain.

A lysophospholipase D (lysoPLD) was purified to apparent homogeneity from rat brain nuclear fractions using 1-[(14)C]palmitoyl-glycerophosphorylcholine as a substrate. The abundance of autotaxin (ATX), a secretory lysoPLD, was also estimated for each fraction. The nuclear fraction had relatively high levels of lysoPLD activity but weak immunoreactivity with an anti-ATX antibody. LysoPLD activity was further purified 5550-fold by sequential chromatography. The final preparation migrated as a single band with a molecular weight of 35,000. Anti-ATX antibodies did not cross-react with the purified enzyme. Moreover, enzyme activity was highest at pH 7.0-7.5 and requires Mg(2+). The Km and Vmax values for 1-palmitoyl-glycerophosphorylcholine were 176 microM and 0.3 micromol/min/mg, respectively. The purified enzyme hydrolyzed saturated forms of LPC more robustly than unsaturated forms. The enzyme could hydrolyze platelet-activating factor (PAF) to the same extent as 16:0-LPC, and showed a higher activity toward lysoPAF (1-O-hexadecyl-2-lyso-glycerophosphorylcholine). These results suggested that the lysoPLD purified from rat brain nuclear fractions in this work is a novel enzyme that hydrolyzes lysoPAF, PAF, and LPC to liberate choline.

Animals↗
PubMed2006

Secretion and lysophospholipase D activity of autotaxin by adipocytes are controlled by N-glycosylation and signal peptidase.

Autotaxin (ATX) is a lysophospholipase D involved in synthesis of lysophosphatidic acid (LPA). ATX is secreted by adipocytes and is associated with adipogenesis and obesity-associated diabetes. Here we have studied the mechanisms involved in biosynthesis and secretion of ATX by mouse 3T3-F442A adipocytes. We found that inhibition of N-glycosylation with tunicamycin or by double point deletion of the amino-acids N53 and N410 of ATX inhibit its secretion. In addition, N-glycosidase treatment and point deletion of the amino-acid N410 inhibits the lysophospholipase D activity of ATX. Analysis of the amino-acid sequence of mouse ATX shows the presence of a N-terminal signal peptide. Treatment with the signal peptidase inhibitor globomycin inhibits ATX secretion by adipocytes. Transfection in Cos-7 cells of site-directed deleted ATX shows that ATX secretion is dependent on the hydrophobic core sequence of the signal peptide, not on the putative signal peptidase cleavage site sequence. Analysis of the amino-acid sequence of mouse ATX also reveals the presence of a putative cleavage site by the protein convertase furin. Treatment of adipocytes with the furin inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone does not modified secretion or lysophospholipase D activity of ATX. Transfection in Cos-7 cells of site-directed deleted ATX shows that the furin recognition site is not required for secretion or lysophospholipase D activity of ATX. In conclusion, the present work demonstrates the crucial role of N-glycosylation in secretion and activity of ATX. The present work also confirms the crucial role signal peptidase in secretion of ATX by adipocytes.

Adipocytes↗
PubMed2002

Lack of significant differences in the corrected activity of lysophospholipase D, producer of phospholipid mediator lysophosphatidic acid, in incubated serum from women with and without ovarian tumors.

BACKGROUND: Several studies have shown that lysophosphatidic acid (LPA), a phospholipidic chemical mediator, is relevant to the pathogenesis of ovarian carcinoma. Higher plasma levels of LPA have been reported in patients with ovarian carcinoma than in healthy patients, and LPA is known to activate ovarian carcinoma cells. To determine the reason for the increased plasma LPA levels in ovarian carcinoma patients, we compared the activities of serum lysophospholipase D, a novel LPA-producing metallo-enzyme, in healthy volunteers, patients with benign ovarian tumor, and patients with ovarian carcinoma. METHODS: Lysophospholipase D activity was assessed by measuring the percentage conversion of [14C]palmitoyl-lysophosphatidylcholine (LPC) added to human serum. The apparent enzyme activities were corrected based on the serum levels of palmitoyl-LPC determined by gas-liquid chromatography after its purification and conversion to fatty acid methyl esters. RESULTS: The apparent activity of lysophospholipase D in serum preparations from four patients with ovarian carcinoma at Stage IV was significantly higher than those from five healthy subjects, five patients with benign ovarian tumors, and fourteen patients with ovarian carcinoma at Stages I (n = 5), II (n = 4), and III (n = 5). The serum levels of LPC, an endogenous substrate of lysophospholipase D, in ovarian carcinoma patients were less than those in patients with benign ovarian tumors. There were no significant differences in the corrected lysophospholipase D activity for the LPC levels in healthy women, patients with benign ovarian tumors, and patients with ovarian carcinoma at various stages. CONCLUSIONS: The current results suggest that lysophospholipase D is not associated with the elevated plasma levels of LPA in ovarian carcinoma patients previously reported, although only a limited number of patients were analyzed.

Adult↗
PubMed2002

Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase.

We purified human plasma lysophospholipase D that produces physiologically active lysophosphatidic acid and showed that it is a soluble form of autotaxin, an ecto-nucleotide pyrophosphatase/phosphodiesterase, originally found as a tumor cell motility-stimulating factor. Its lower K(m) value for a lysophosphatidylcholine than that for a synthetic substrate of nucleotide suggests that lysophosphatidylcholine is a more likely physiological substrate for autotaxin and that its predicted physiological and pathophysiological functions could be mediated by its activity to produce lysophosphate acid, an intercellular mediator. Recombinant autotaxin was found to have lysophospholipase D activity; its substrate specificity and metal ion requirement were the same as those of the purified plasma enzyme. The activity of lysophospholipase D for exogenous lysophosphatidylcholine in human serum was found to increase in normal pregnant women at the third trimester of pregnancy and to a higher extent in patients in threatened preterm delivery, suggesting its roles in induction of parturition.

Amino Acid Sequence↗
PubMed2002

Physiological and pathophysiological roles of lysophosphatidic acids produced by secretory lysophospholipase D in body fluids.

Recently, a family of phospholipid mediators has received much attention because of its variety of biological activities. Lysophosphatidic acid (LPA) is a central member of the phospholipid autacoid family that exerts diverse effects through binding to and activation of several specific receptors coupled to G-proteins. In accordance with its function as a receptor agonist, there are pathways for extracellular generation of LPA in vivo. One pathway involves a novel lysophospholipase D activity that was originally found in rat plasma. LPA is also produced in significant amounts after incubation of various plasma-derived body fluids such as human follicular fluid at 25-37 degrees C. In animal models, LPA was shown to stimulate oocyte maturation, embryonic development and transport in the oviduct. An increase in serum lysophospholipase D activity was observed during pregnancy in human. These results suggest that LPA generated by lysophospholipase D is likely to play an important role in reproductive biology. LPA produced by lysophospholipase D activity in body fluids has also been observed under pathophysiological conditions: serum and ascitic fluid from ovarian cancer patients and serum from hypercholesterolemic rabbits. Hence, excess generation of LPA by lysophospholipase D activity in body fluids has been suggested to be relevant to the pathogenesis of cancer and atherosclerosis.

Animals↗
PubMed2002

Increased production of bioactive lysophosphatidic acid by serum lysophospholipase D in human pregnancy.

Lysophosphatidic acid (LPA) is a prototype of the lysophospholipid mediator family and has multiple effects in the female reproductive system. Although several metabolic routes have been reported for intracellular formation of LPA, a unique route involving lysophospholipase D, an extracellular enzyme that produces LPA in blood and body fluids, is particularly intriguing for its agonistic role. In this study, using an assay with radioactive palmitoyl-lysophosphatidylcholine, we found that lysophospholipase D activity producing palmitoyl-LPA in human serum gradually increased during pregnancy. Elevated activity of lysophospholipase D was not caused by changes in levels of their precursors, lysophosphatidylcholines, in nonpregnant women or in pregnant women at different gestational periods. With increasing length of gestation, the elevated activity in pregnant women was found to produce increasing proportions of LPA with a palmitoyl group versus other LPAs. These results suggest that LPA formed by increased activity of lysophospholipase D in blood might participate in maintenance of pregnancy.

Adult↗
PubMed2002

Increased formation of lysophosphatidic acids by lysophospholipase D in serum of hypercholesterolemic rabbits.

Lysophosphatidic acid (LPA) is a biologically active phospholipid that has been identified as a vasoactive principle in incubated plasma and serum of mammals. Previously, we found that mammalian plasma and serum contain a lysophospholipase D, which hydrolyzes lysophosphatidylcholines (LPCs) with different fatty acyl groups to the corresponding LPAs during its incubation at 37 degree C. In this study, we examined whether lysophospholipase D activity and levels of LPCs in rabbit serum were modulated by feeding rabbits a high cholesterol diet. Results showed that the serum levels of LPCs increased gradually in animals fed a high cholesterol diet for 12 weeks. We found that the levels of individual LPAs formed on incubation of serum for 24 h increased with an increase in the period of feeding of rabbits a high cholesterol diet. LPA with a linoleate residue was the most abundant LPA, followed in order by 16:0-, 18:1- and 18:0-LPAs. LPA was found to increase attachment of the monocytic cell line THP-1 to vascular endothelial cells pre-stimulated with tumor necrosis factor-alpha. These results indicated that increases in the levels of LPAs generated by lysophospholipase D in the blood of hypercholesterolemic rabbits may be relevant to attachment of monocytes to vascular walls, a key phenomenon observed at an early stage of atherosclerosis.

Animals↗
PubMed1995

Metabolic fate of platelet-activating factor in the rat enterocyte: the role of a specific lysophospholipase D.

The metabolism of platelet-activating factor (PAF) by isolated rat intestinal epithelial cells was investigated using 1-[3H]octadecyl-2-acetyl-sn-glycero-3-phosphocholine. The principal metabolite produced by the cells was 1-O-alkylglycerol, which was found in association with the cells and the medium. When similar studies were conducted employing an intestinal epithelial cell line (INT 407), PAF was almost quantitatively converted into 1-alkyl-2-acyl-sn-glycero-3-phosphocholine (AAGPC). When the intestinal epithelial cell microsomes were incubated in the presence of fluoride to inhibit phosphohydrolase activity, the formation of 1-alkylglycerol was decreased in association with a stoichiometric increase in 1-alkyl-glycerophosphate, indicating the presence of a lysophospholipase D in the intestinal cells. When the phospholipase D activity was examined in the microsomal fraction prepared from intestinal epithelial cells, lyso-PAF was the preferred substrate and only trace amounts of lyso-PAF were converted into alkylacyl-GPC. Acyllyso-GPC was rapidly cleaved to form free fatty acids. The absence of lysophospholipase D activity in INT 407 cells cannot be attributed to the absence of brush border in these cells since no lysophospholipase D activity was present in isolated brush border preparations.

Animals↗
PubMed1986

Involvement of lysophospholipase D in the production of lysophosphatidic acid in rat plasma.

A vasoactive lipid present in rat plasma that had been incubated at 37 degrees C for 48 h was identified as lysophosphatidic acid with the following fatty acid composition: palmitic acid (25.2%), stearic acid (8.4%), oleic acid (7.0%), linoleic acid (44.4%) and arachidonic acid (11.9%). The involvement of lysophospholipase D in the production of lysophosphatidic acid was suggested on the basis of extensive analyses of phospholipids in the plasma. Results indicated that lysophospholipase D hydrolyzed polyunsaturated lysophosphatidylcholines preferentially to the saturated species. Exogenously added platelet activating factor was found to be first converted to its lyso derivative by an acetylhydrolase in rat plasma and then degraded by lysophospholipase D to 1-alkyllysophosphatidic acid to a similar extent with exogenously added lyso derivative of platelet activating factor; their percent conversions to lysophosphatidic acid were higher than those of saturated 1-acyllysophosphatidylcholines, but lower than those of polyunsaturated 1-acyllysophosphatidylcholines.

Animals↗
PubMed2005

Proteolytic maturation and activation of autotaxin (NPP2), a secreted metastasis-enhancing lysophospholipase D.

Autotaxin (NPP2) is an extracellular protein that is upregulated in various malignancies, including breast and lung cancer. It potently stimulates cell proliferation, cell motility and angiogenesis, which is accounted for by its intrinsic lysophospholipase-D activity that generates the lipid mediators lysophosphatidic acid and sphingosine-1-phosphate. Based on its structural similarities with the better characterized nucleotide pyrophosphatase/phosphodiesterase NPP1, it has always been assumed that NPP2 is also synthesized as a type-II integral membrane protein and that extracellular NPP2 is generated from this membrane precursor. We show here, however, using domain swapping and mutagenesis experiments as well as N-terminal protein sequencing, that NPP2 is actually synthesized as a pre-pro-enzyme and that the proteolytically processed protein is secreted. Following the removal of a 27-residue signal peptide by the signal peptidase, NPP2 is subsequently cleaved by proprotein convertases (PCs). The removal of an N-terminal octapeptide by PCs is associated with an enhanced activity of NPP2 as a lysophospholipase D. These novel insights in the maturation of NPP2 have also implications for the development of NPP2 inhibitors as potential anti-cancer agents.

Amino Acid Sequence↗
PubMed1998

Metal-ion stimulation and inhibition of lysophospholipase D which generates bioactive lysophosphatidic acid in rat plasma.

We found that lysophospholipase D (LPLD) in rat plasma prefers unsaturated to saturated lysophosphatidylcholines as substrates, generating a biologically active lipid, lysophosphatidic acid, but it does not hydrolyze diacyl-phospholipids. In this study, this LPLD required a metal ion for activity, Co2+ being the most effective, followed in order by Zn2+, Mn2+, and Ni2+. This metal-ion-stimulated LPLD with unique substrate specificity, which has not been described previously, was susceptible to thiol-blocking reagents and serine esterase inhibitors, but not to a histidine-modifying reagent. Consistent with results using thiol-modifying agents, short-chain fatty aldehydes, secondary products of lipid peroxidation, were found to inhibit LPLD. Addition of dibutylhydroxytoluene or butylhydroxyanisole to the plasma increased the activity of this enzyme, probably in a manner independent of its antioxidant activity, since another antioxidant, propyl gallate, was rather inhibitory. These results suggest that rat plasma contains an active LPLD that differs in some properties from other members of the known phospholipase D family detected in animal tissues and body fluids.

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed2006

Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development.

Autotaxin (ATX), or nucleotide pyrophosphatase-phosphodiesterase 2, is a secreted lysophospholipase D that promotes cell migration, metastasis, and angiogenesis. ATX generates lysophosphatidic acid (LPA), a lipid mitogen and motility factor that acts on several G protein-coupled receptors. Here we report that ATX-deficient mice die at embryonic day 9.5 (E9.5) with profound vascular defects in yolk sac and embryo resembling the Galpha13 knockout phenotype. Furthermore, at E8.5, ATX-deficient embryos showed allantois malformation, neural tube defects, and asymmetric headfolds. The onset of these abnormalities coincided with increased expression of ATX and LPA receptors in normal embryos. ATX heterozygous mice appear healthy but show half-normal ATX activity and plasma LPA levels. Our results reveal a critical role for ATX in vascular development, indicate that ATX is the major LPA-producing enzyme in vivo, and suggest that the vascular defects in ATX-deficient embryos may be explained by loss of LPA signaling through Galpha13.

Animals↗
PubMed1999

Production of lysophosphatidic acid by lysophospholipase D in incubated plasma of spontaneously hypertensive rats and Wistar Kyoto rats.

Lysophosphatidic acid has been identified as a vasopressor principle in incubated mammalian plasma and sera, and shown to be generated extracellulary by lysophospholipase D-like activity. In this study, we monitored the time course of changes in the major phospholipid fractions during incubation of plasma, and found that polyunsaturated lysophosphatidic acids accumulate more rapidly than saturated lysophosphatidic acids at expense of the corresponding lysophosphatidylcholines. We compared the phospholipase activities for producing bioactive LPA in age-matched spontaneously hypertensive rats and Wistar Kyoto rats. The lysophospholipase D activity in rat plasma was found to be independent of strain and age. We suggest that lysophospholipase D functions in rat for persistent production of bioactive LPA in the circulation throughout life. However, our finding that production of LPA in spontaneously hypertensive rats was not greater than that in Wistar Kyoto rats does not seem to support the idea that increased production of LPA is involved in the pathogenesis of hypertension.

Aging↗
PubMed2004

Lysophospholipase D and its role in LPA production.

Lysophosphatidic acid (LPA) is an important lipid mediator that binds to G-protein-coupled receptors of the Edg family, inducing proliferation and migration in many cell lines. Much has been learned about pathways involved in LPA signaling, but the pathways responsible for LPA production remain to be fully resolved. Several potential routes have been proposed for LPA production. One involves the sequential actions of phopholipase D (PLD) and phospholipase A(2) (PLA(2)). Another route involves the sequential actions of PLA(2) and lysophospholipase D (lysoPLD). LysoPLD is defined as an enzyme which hydrolyzes lysophospholipids to produce LPA. Two major forms of lysoPLD, microsomal and extracellular forms, have been reported. A microsomal lysoPLD plays an important role in the metabolism of platelet-activating factor (PAF) because of its preference for alkyl-phospholipids. The extracellular form of lysoPLD coexists with its substrate, lysophosphatidylcholine (LPC), in the extracellular compartment. LysoPLDs purified from the extracellular space have recently been shown to be molecularly identical to autotaxin (ATX). ATX, an enzyme previously known to possess 5'-nucleotide pyrophosphatase and phosphodiesterase (PDE) activities, was subsequently shown to have lysoPLD activity. The unexpected linkage of the extracellular lysoPLD with ATX has raised many interesting questions. The characterization and purification of lysoPLDs are reviewed here.

Animals↗
PubMed2003

Site-directed mutations in the tumor-associated cytokine, autotaxin, eliminate nucleotide phosphodiesterase, lysophospholipase D, and motogenic activities.

The exo-enzyme autotaxin/NPP2 (ATX/NPP2) is a potent stimulator of cell migration, invasion, metastasis, and angiogenesis. Recently, ATX/NPP2 was found to possess lysophospholipase D (lyso-LPD) activity, generating the bioactive mediator lysophosphatidic acid from precursors. In the present study, we used site-directed mutagenesis to delineate the active domain of lysophospholipid catalytic activity and to examine potential overlap with the nucleotide phosphodiesterase domain. We found four amino acid residues obligatory for the phosphodiesterase, lyso-PLD, and migration-stimulating activities of ATX/NPP2, suggesting that 5'-nucleotide phosphodiesterase (PDE) and lyso-PLD share a common reaction mechanism and inviting design of enzymatic inhibitors as therapeutic agents for neoplastic disease.

Animals↗