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PubMed1993

Induction of exocrine pancreas maturation at weaning in young developing pigs.

The influence of weaning, at either 4 or 6 weeks of age, on the maturation of the exocrine pancreas was studied in naturally reared Swedish Landrace pigs that had no access to solid food. The pigs were surgically fitted with chronic catheters at 3 weeks of age, permitting periodic sampling of pancreatic juice and blood in conscious animals < or = 4 weeks after weaning. During the suckling period, pancreatic fluid and enzyme secretion remained low, both before (preprandial) and after (postprandial) milk ingestion. After weaning at 4 or 6 weeks of age, juice secretion, output of total protein, and levels of different hydrolases (amylase, trypsin, lipase, and carboxylester lipase) and the cofactor colipase all increased markedly postprandially. Moreover, after weaning, the plasma insulin level increased postprandially. This did not happen before weaning, although blood glucose levels always rose after feeding. The data showed a relationship between the time of weaning and the induction of exocrine pancreatic maturation in pigs. This finding implies that postnatal development of pancreatic function is triggered by the dietary change from sow milk to dry solid food. In contrast, the age of the pig appears to be of minor importance, since weaning at either 4 or 6 weeks of age gave a similar result.

Animals↗
PubMed2004

Crystallization of a proteolyzed form of the horse pancreatic lipase-related protein 2: structural basis for the specific detergent requirement.

Horse pancreatic lipase-related proteins PLRP1 and PLRP2 are produced by the pancreas together with pancreatic lipase (PL). Sequence-comparison analyses reveal that the three proteins possess the same two-domain organization: an N-terminal catalytic domain and a C-terminal domain, which in PL is involved in colipase binding. Nevertheless, despite the high level of sequence identity found, they exhibit distinct enzymatic properties. The intrinsic sensitivity of the peptide bond between Ser245 and Thr246 within the flap region of PLRP2 to proteolytic cleavage probably complicates PLRP2 crystallization since, as shown here, this proteolyzed form of PLRP2 is only crystallized after specific detergent stabilization of this region. This has been performed by the hanging-drop vapour-diffusion method at 291 K and exclusively in the presence of N,N-dimethyldecylamine-beta-oxide (DDAO). However, most crystals (>95%) are highly twinned and diffract poorly (to approximately 7-5 A resolution). Diffraction-quality trigonal crystals have unit-cell parameters a = b = 128.4, c = 85.8 A and belong to space group P3(2)21. A 2.9 A native data set was collected at ESRF on beamline ID14-2 with an R(merge) of 12.7%. Preliminary structural analysis provides a structural basis for the specific roles of DDAO.

Animals↗
PubMed1976

Esterolytic activities of rat intestinal mucosa. 2. Purification and properties of a glycerol-ester hydrolase.

A glycerol-ester hydrolase from rat intestinal cells has been purified using chromatography on carboxyhexanoyl-Sepharose-glyceryldioctanoate and preparative gel electrophoresis. The enzyme gives a single band by analytical gel electrophoresis; it is a monomer of molecular weight 68000. The optimum pH for its action on glyceryl tributyrate is between 8.0 and 8.5; the activation energy was calculated to be 8.7 kcal x mol-1 (36.4 kJ/mol). Its substrate specificity is mainly directed against esters of glycerol and of primary monoalcohols. Similarly to pancreatic lipase but contrary to liver esterase, it is inhibited by bile salts; relief of this inhibition by colipase is only observed for pancreatic lipase. The possible role of the glycerol-ester hydrolase in the absorption of short and of medium chain triglycerides is discussed.

Animals↗
PubMed1989

Changes in mRNA levels of rat pancreatic lipase in the early days of consumption of a high-lipid diet.

The time-course response of rat pancreatic enzymes to a diet containing 25% sunflower oil was investigated. A 1.2-fold enhancement in lipase specific activity was observed as early as the first day of diet consumption and was further increased up to 1.9-fold on the 5th day. On the other hand, colipase activity was slightly decreased during the first two days of high-lipid diet intake and then increased. An immediate and direct effect was also exerted by the 25% lipid diet on lipase biosynthesis. Both fractional synthetic rate and specific activity of lipase were comparably induced. Due to a 1.6-fold increase in the overall protein synthesis following 5 days of lipid diet consumption, the absolute synthesis of lipase and amylase was increased by 3.5-fold and 0.98-fold, respectively, as compared to control animals. By contrast, the synthesis of procarboxypeptidases and serine proteases did not increase before day 5, probably as the result of a distinct adaptive mechanism. The pancreatic mRNA levels in control and adapted animals, which were determined by dot-blot hybridization with amylase and lipase cDNAs, were consistent with a biphasic induction of lipase synthesis since a first increase in the level of the enzyme-specific mRNA during the first two days of diet intake (4-fold on day 1) was followed by a second increase after the fourth day (6.5-fold on day 5). On the other hand, amylase mRNA level was unchanged during the dietary manipulation. Thus, hyperlipidic diets exerted an both lipase activity and synthesis but a delayed effect on procarboxypeptidase and serine protease synthesis. In a similar manner, the immediate induction of lipase mRNA level by dietary fat, followed by another increase a few days later, suggested that at least two different mechanisms are involved in lipase mRNA induction.

Amylases↗
PubMed1981

Lipid absorption and intestinal lipoprotein formation.

Lipid absorption is a complex process which involves coordinated gastric, intestinal, biliary and pancreatic function. Emulsification of dietary lipid occurs in the stomach and upper intestine where a series of enzymic events also occur. Phospholipids are digested by phospholipases. Colipase anchors lipase to the emulsion surface overcoming the interfering effect of bile salts. The products of lipolysis, monoglycerides and fatty acids, are removed from the emulsion surface by bile salts in the form of mixed micelles which transport lipid digestive products across the unstirred water layer to the epithelial cell. Within the intestinal epithelial cell a series of synthetic events occur resulting in the formation of chylomicrons and very low density lipoprotein (VLDL). Chylomicrons consists of an oily core of triglyceride surrounded by a membrane of phospholipids, free cholesterol and apoproteins which maintain the solubility of the particle in plasma. Chylomicrons from both experimental animals and man have specific apoproteins associated with them. These proteins include apoA-I, the major protein of plasma high density lipoproteins. During chylomicron metabolism, apoA-I and phospholipid from the chylomicron surface contribute to plasma high density lipoproteins. Other chylomicron apoproteins include apoB and apoA-IV, which are synthesized in the intestine, and apoC and apoE which are absorbed onto the chylomicron surface from other lipoproteins. The intestines also synthesizes, very low density sized particles (VLDL) while fasting and during lipid absorption. There is evidence that the intestine also synthesizes high density lipoproteins. The intestine has recently been recognized as a major site of synthesis of plasma lipoproteins and apoproteins, especially apoA-I for plasma high density lipoproteins.

Apoproteins↗
PubMed2004

Structural determinants required for the bioactivities of prokineticins and identification of prokineticin receptor antagonists.

Prokineticins are cysteine-rich secreted proteins that regulate diverse biological processes, including gastrointestinal motility, angiogenesis, and circadian rhythms. Two closely related G protein-coupled receptors that mediate signal transduction of prokineticins have recently been cloned. The structural elements required for prokineticins' bioactivities are still unknown. We show here that both the N-terminal hexapeptide (AVITGA) and C-terminal cysteine-rich domains are critical for the bioactivities of prokineticins. Substitutions, deletions, and insertions to the conserved N-terminal hexapeptides result in the loss of agonist activity. Mutant prokineticins with the substitution of the first N-terminal alanine with methionine or the addition of a methionine to the N terminus inhibit the activation of prokineticin receptors and thus are considered as antagonists of prokineticin receptors. We have further shown that mutations in selected cysteine residues in the C-terminal domain result in prokineticins without biological activity. The essential role of C-terminal domain is reinforced by two observations: that peptides without the carboxyl domain and proteins with the N-terminal hexapeptide fused to the carboxyl domains of colipase or dickkopf are devoid of biological activity. We demonstrate that limited structural changes of C-terminal cysteine-rich regions of prokineticins are tolerable because chimeric prokineticins with swapped cysteine-rich domains between prokineticin 1 and prokineticin 2, as well as a splice variant of prokineticin 2 that contains extra 21 residue insertion in its C-terminal domain, are biologically active.

Alternative Splicing↗
PubMed1993

Lipid absorption: passing through the unstirred layers, brush-border membrane, and beyond.

Lipids are components of our diet and luminal secretions, with physicochemical characteristics that determine their digestion and absorption in the gastrointestinal tract. Lipids include triglycerides, phospholipids, and cholesterol. Dietary lipids contain approximately 97% triglycerides, with small amounts of phospholipids and cholesterol. These components are important in cell membrane composition, fluidity, peroxidation, prostaglandin and leukotriene synthesis, and cellular metabolic processes. Lipids are implicated in the mechanisms of brain development, inflammatory processes, atherosclerosis, carcinogenesis, aging, and cell renewal. Duodenal hydrolysis of dietary lipids and biliary phospholipids and cholesterol is carried out by pancreatic lipase, colipase, phospholipase A2, and cholesterol esterase. Bile acid solubilization results in mixed micelles and liposomes, in gel and liquid crystal phases. Lipid digestion products pass across the intestinal unstirred water layer. For long-chain fatty acids and cholesterol, passage across the unstirred water layer is rate limiting, whereas passage of short- and medium-chain fatty acids is limited by the brush-border membrane. Within the unstirred water layer, an acidic microclimate aids micellar dissociation so that protonated, and to a lesser extent, nonprotonated monomers then pass across the intestinal brush-border membrane. Absorptive mechanisms have been studied extensively in relation to lipid composition, fatty acid chain length, degree of unsaturation, essential fatty acid content, phospholipid components, and cholesterol. Enterocytes may take up lipids from the intestinal lumen or from lipoproteins of the bloodstream, but these pools are likely to be functionally distinct. Recent advances are reviewed, including recent advances in the area of microclimates, compartmentation, lipid binding proteins, intracellular trafficking, intestinal lipoproteins, release of lipids across the basolateral membrane, and dietary effects.

Bile Acids and Salts↗
PubMed1996

Dexamethasone-regulated expression of pancreatic lipase and two related proteins in AR42J cells.

The pancreas makes two pancreatic proteins [pancreatic lipase-related protein-1 (PLRP-1) and PLRP-2] with marked homology to pancreatic lipase (PL). To determine if a pancreatic acinar cell line, AR42J, also expresses PLRP-1 and PLRP-2, we examined the cells for the presence of PL, PLRP-1, and PLRP-2. RNA blot analysis with specific probes and immunoblot analysis with antipeptide antibodies demonstrated the presence of mRNA and protein for all three homologues in AR42J cells. Additionally, we showed that dexamethasone decreased PLRP-1 mRNA levels twofold and increased PLRP-2 mRNA 20-fold but had little effect on PL or colipase mRNA. Extracellular PLRP-2 protein levels increased threefold, and intracellular PLRP-2 protein levels increased about fourfold. The characteristics of the dexamethasone-induced increase in PLRP-2 mRNA, a rapid change requiring new protein synthesis independent of mRNA turnover, suggested that dexamethasone regulated transcription. We conclude that AR42J cells synthesize and secrete PL, PLRP-1, and PLRP-2 and that dexamethasone discoordinately regulates the expression of the three genes.

Animals↗
PubMed1984

Fat digestion by lingual lipase: mechanism of lipolysis in the stomach and upper small intestine.

Ten to 30% of dietary fat is hydrolyzed in the stomach by lingual lipase, an enzyme secreted from lingual serous glands. We investigated the substrate specificity of this enzyme as well as the potential of lingual lipase to act in the upper small intestine i.e., in the presence of bile salts and lecithin. The data presented show that partially purified preparations of rat lingual lipase and the lipase in gastric aspirates of newborn infants have identical substrate specificity: medium-chain triglycerides were hydrolyzed at rates 5-8-fold higher than long-chain triglycerides; the rat and human enzymes do not hydrolyze the ester bond of lecithin or cholesteryl-ester. In contrast to pancreatic lipase, the hydrolysis of triglycerides by lingual lipase is not inhibited by lecithin. But, similar to pancreatic lipase the activity of lingual lipase is inhibited by bile salts, the extent of inhibition varying with its nature and concentration. This inactivation is not prevented by colipase but is partially averted by lipids and protein, suggesting that lingual lipase can remain active in the duodenum. The pH optimum of the enzyme (2.2-6.5 in the rat and 3.5-6.0 in human gastric aspirates) is compatible with continued activity in the upper small intestine, especially during the neonatal period, when the luminal pH is under 6.5. The marked variation in lipase activity levels in gastric aspirates of newborn infants is probably due to individual variations in enzyme amounts. The characteristics of the lipase are however identical in infants with low, intermediate or high activity levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗
PubMed1993

Study of mechanism of lipolysis inhibition by bovine milk proteose-peptone component 3.

Milk component 3 was an inhibitor of lipoprotein lipase activity responsible for spontaneous lipolysis occurring in milk stored at 4 degrees C. Experiments using a pH-stat apparatus and emulsified tributyrin showed that component 3 inhibited porcine pancreatic lipase. The lipolytic activity was fully restored by addition of sodium taurodeoxycholate and colipase to the emulsion containing component 3. Inhibition did not seem to be the result of a direct interaction between component 3 and the enzyme. Component 3 had a strong adsorption power superior to that of pancreatic lipase, as shown by tensiometric measurements at an n-tetradecane-water interface. Lipase inhibition by component 3 could be the consequence of a rapid diffusion and preferential adsorption of component 3 at the oil-water interface provoking an important decrease of interfacial tension and avoiding the adsorption of lipase.

Adsorption↗
PubMed2000

Characterization of the human peroxisome proliferator activated receptor delta gene and its expression.

Peroxisome proliferator activated receptors (PPARs) are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. Three different PPARs; alpha (PPARA), gamma (PPARG) and delta (PPARD) have been characterized and they are distinguished from each other by tissue distribution and cell activation. In this study, the structure and detailed chromosomal localization of the human PPARD gene was determined. Three genomic clones containing the PPARD gene was isolated from a human P1 library. The gene spans approximately 85 kb of DNA and consists of 9 exons and 8 introns with exons ranging in size from 84 bp to 2.3 kb and introns ranging from 180 bp to 50 kb. All splice acceptor and donor sites conform to the consensus sequences including the AG-GT motif. Although PPARD lacks a TATA box, the gene is transcribed from a unique start site located 380 bp upstream of the ATG initiation codon. The 5' and 3' ends were mapped by rapid amplification of cDNA ends and the mRNA size of PPARD based upon the structure of the gene is 3803 bp. In addition, the chromosomal sublocalization of PPARD was determined by radiation hybrid mapping. The PPARD gene is located at 14 cR from the colipase gene and 15 cR from the serine kinase gene at chromosomal region 6p21.2.

Adult↗
PubMed1996

What is the best biochemical test to diagnose acute pancreatitis? A prospective clinical study.

OBJECTIVE: To determine which biochemical test is best to distinguish acute pancreatitis from other pancreatic and nonpancreatic diseases associated with hyperamylasemia. DESIGN: We conducted a prospective clinical study of 836 consecutive patients who had a total serum amylase test requested by a physician during a 7-month period. MATERIAL AND METHODS: Radioimmunoassay and enzymatic activity methods were used to measure pancreas-specific proteins of varied size, charge, and stability. In addition, scoring systems were used for the diagnosis of pancreatitis, and statistical analyses were done to determine sensitivity and specificity. RESULTS: We found minor differences in sensitivity and specificity for diagnosis of acute pancreatitis among pancreatic isoamylase, phospholipase A2, colipase, lipase, and carboxylester lipase. Of these tests, the combination of isoamylase and phospholipase A2 had a small but statistically significant increased sensitivity (90%; 95% confidence interval [CI] = 74 to 98%) and specificity (93%; 95% CI = 91 to 95%) over isoamylase (90% and 92%, respectively; 95% CI = 90 to 94%) and phospholipase A2 (90% and 75%, respectively; 95% CI = 72 to 78%) alone for the diagnosis of acute pancreatitis. CONCLUSION: Pancreas-specific proteins are satisfactory for diagnosing acute pancreatitis if the test is validated by the laboratory. Clinically, the slight advantage of using both isoamylase and phospholipase A2 does not outweigh the expense of performing two assays; we recommend using isoamylase to diagnose acute pancreatitis.

Acute Disease↗
PubMed1985

Acute pancreatitis.

The exocrine pancreas secretes into the gut on demand more than 20 proteins that are indispensable for digestion. In-vivo autodigestion is prevented by an array of natural safeguards. In acute pancreatitis, inappropriate intrapancreatic activation and release of pancreatic hydrolases occur, but the pathogenetic mechanism of autodigestion is unclear. The release of proteases, lipase and colipase, phospholipase A, vasoactive peptides, and other agents probably accounts for the edema, tissue destruction, fat necrosis, metabolic abnormalities, and complications. Ethyl alcohol abuse, gallstones, trauma, and other common and rare conditions can induce pancreatitis. The patient's outcome can be predicted by certain prognostic signs. Ultrasonography and computerized tomography are invaluable diagnostic tools and magnetic resonance imaging appears promising. Hemodynamic monitoring, intensive care with colloid and crystalloid infusions, correction of electrolyte abnormalities, judicious use of antibiotics, peritoneal lavage, drainage of pancreatic exudation fluids, and surgical intervention require a team approach, especially in patients with multiple complications. Additional research is needed into the pathogenetic mechanism of autodigestion and the design of specific therapies.

Abscess↗
PubMed2000

Effect of increasing lipid loads on the ability of the endoplasmic reticulum to transport lipid to the Golgi.

We have previously shown (Mansbach, C. M. and P. J. Nevin, 1998. J. Lipid Res. 39: 963;-968) that after the development of a mass steady state with respect to triacylglycerol absorption in rats, the introduction of radiolabeled trioleoylglycerol, while maintaining the input rate of trioleoylglycerol constant at 135 micromol/h, was followed by a slow (60 min) achievement of a radiolabel steady state in the intestinal endoplasmic reticulum (ER). We hypothesized that this was due to the large input load and that the time to steady state would be shorter at lower lipid loads. Rats were infused intraduodenally with 22.5, 45, 90, or 135 micromol trioleoylglycerol/h for 6 h to obtain a mass steady state in the intestine. [(3)H]trioleoylglycerol was added to the infusate and the ER and Golgi were isolated from the proximal intestine after 5;-60 min of radiolabel infusion. The time required to reach a radiolabel steady state in the ER lengthened from 10 min at the 22.5 micromol/h infusion rate to 60 min at the 135 micromol/h rate. Similar data were obtained for the Golgi. Incubation of the ER with lipase reduced the ER;-triacylglycerol amount by 43% and increased its specific activity by 73%. The amount of [(3)H]TG-dpm in the ER was not reduced unless taurocholate, 10 mm, and colipase were added. We conclude that as the rate of triacylglycerol infusion is increased, TG movement from the ER to the Golgi progressively lengthens until finally all the triacylglycerol infused cannot be transported. A portion of this triacylglycerol is disposed on the cytoplasmic face of the ER and thus able to be attacked by lipase whereas another fraction is sequestered in the ER lumen and immune to lipase attack unless the ER membrane is solubilized.

Animals↗
PubMed2001

Commutability of calibration and control materials for serum lipase.

BACKGROUND: To effectively assess and correct for intermethod variability, calibration and control materials (CCMs) must show the same intermethod behavior as patient sera, i.e., they must be commutable. We describe the commutability of selected CCMs for lipase assays, the impact of noncommutability of CCMs in normalizing patient results, and characteristics of reagents that affect assay specificity and commutability. METHODS: Lipase was measured in 98 patient sera and in 29 commercial CCMs, with 2 commercial methods using different substrates and with 4 experimental methods using 1,2-o-dilauryl-rac-glycero-3-glutaric acid-(6'-methylresorufin) ester as substrate and colipase as cofactor, but differing in the stabilizing proteins used and in the size of the substrate micelles. RESULTS: The noncommutability rate, i.e., the frequency of aberrant intermethod behavior of CCMs in comparison with patient sera, was 27% for liquid CCMs and 47% for lyophilized CCMs. The normalized residuals, measuring the degree of noncommutability, were -2.3 to 2.4 for CCMs with "normal" lipase activity, and -3.5 to 21.7 for CCMs with higher lipase activity. Recalculation of patient results with CCMs as calibrators decreased or increased the original bias according to whether the CCMs were commutable. CONCLUSIONS: For the lipase methods in this study, the frequency of noncommutability of CCMs is affected by assay-specific characteristics, including size of substrate micelles and the presence or absence of added proteins.

Calibration↗
PubMed1992

Lateral lipid distribution is a major regulator of lipase activity. Implications for lipid-mediated signal transduction.

Pancreatic carboxylester lipase catalyzes the exchange of 18O between water and 13,16-cis,cis-doco-sadienoic acid (DA) in monolayers at the argon-buffer interface (Muderhwa, J.M., Schmid, P.C., and Brockman, H.L. (1992) Biochemistry 31, 141). In mixed monolayers of 18O, 18O-DA and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), both the extent and mechanism of 18O exchange show characteristics of a critical transition in the range of 0.5-0.6 mol fraction of DA (Muderhwa, J.M., and Brockman, H. L. (1992) Biochemistry 31, 149). To determine if the regulatory behavior exhibited on this type of surface is limited to members of the carboxylester lipase gene family (cholinesterases), comparable experiments were performed with a genetically and functionally unrelated lipase, pancreatic colipase-dependent lipase (PL). PL readily catalyzed the exchange of 18O between water and the carboxyl group of DA with enzyme at either monolayer or catalytic levels in the fatty acid-buffer interface. The oxygen exchange reaction obeyed a random, sequential mechanism, indicating that the dissociation of the enzyme.DA complex is much faster than the rate-limiting step in the overall exchange process. Kinetic analysis of oxygen exchange in pure DA monolayers showed a first-order dependence on interfacial PL and DA concentrations from which kcat/Km values were calculated. The oxygen exchange reaction proceeded with a rate constant of 16 x 10(-2) cm2 pmol-1 s-1, a value comparable to that for hydrolysis of the ester substrate, 1,3-dioleoylglycerol. With a monolayer of PL adsorbed to the interfacial phase, kcat/Km for oxygen exchange was about 600-fold lower than the value obtained with catalytic levels of adsorbed enzyme, indicating a possible restriction of substrate diffusion in the protein-covered fatty acid monolayer. With constant bulk PL concentration and mixed lipid monolayers containing DA and the non-substrate lipid, POPC, the extent of oxygen exchange increased abruptly as the abundance of DA in the interface was increased from 0.5 to 0.6 mol fraction. Concomitant with this critical transition was a change in the apparent mechanism of oxygen exchange from coupled to random, sequential. For both the extent of oxygen exchange and its mechanism shift, the critical transition was independent of the lipid packing density, i.e. surface pressure, of the interface. These results show that PL responds similarly to carboxylester lipase with respect to changes in interfacial lipid mole fraction in DA-POPC surfaces.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Spectrophotometric determination of lipase activity in the presence of increased triolein concentration.

A novel approach for the determination of pancreatic lipase (EC 3.1.1.3) activity by a spectrophotometric method is described. Enzyme activity is measured in the presence of 1 mmol/l triolein, a concentration much higher than usually employed in turbidimetry. The primary reaction medium is optimized as regards bile salt and colipase concentrations. The released fatty acids are enzymatically determined via a secondary reaction scheme using the constituents of a commercially available kit. The proposed method is easy to perform and may prove useful in determining lipase activity of standard lipase preparations, which is required for indirect assays. In addition to satisfactory precision and linearity as well as close correlation with other lipase assays, the procedure described in the present paper by-passes a number of short-comings (eg uncontrolled increase in absorbance) inherent to the turbidimetric methods.

Adult↗
PubMed1991

Effects of gene mutations in lipoprotein and hepatic lipases as interpreted by a molecular model of the pancreatic triglyceride lipase.

A molecular model of human pancreatic lipase (Winkler, F. K., D'Arcy, A., and Hunziker, W. (1990) Nature 343, 771-774) is used to explain the possible structural effects of the amino acid mutations identified to date in the human lipoprotein and hepatic lipase genes. A sequence homology profile was used to evaluate the alignment of the amino acid sequences of all three lipolytic enzymes (Kirchgessner, T. G., Chuat, J.-C., Heinzmann, C., Etienne, J., Guilhot, S., Svenson, K., Ameis, D., Pilon, C., D'Auriol, L., Andalibi, A., Schotz, M. C., Galibert, F., and Lusis, A. J. (1989) Proc. Natl. Acad. Sci. U. S. A. 86, 9647-9651) with respect to the secondary structure elements identified in the pancreatic lipase. As expected, maximum homology is observed in internal regions namely the hydrophobic strands of the central beta-pleated sheet. This observation strongly supports the hypothesis that all three molecules exhibit a very similar three-dimensional structure, particularly in the N-terminal catalytic domain. There is considerable variation in some of the surface loops connecting the individual strands, whereas others are conserved. It is hypothesized that the most conserved loops located around the active site are responsible for the catalytic function (similar for all three enzymes), whereas those that markedly differ are involved in the regulation at the molecular level, namely the binding of colipase (pancreatic enzyme) and apolipoprotein CII (lipoprotein lipase). The currently available library of hepatic and lipoprotein gene mutations seems to indicate that the majority of mutants disrupt the folding of the polypeptide chain, rather than affect specific constellations in and around the catalytic site or regulatory loops.

Amino Acid Sequence↗