Lingual lipase
Encyclopedia
Lingual lipase is a member of a family of digestive enzyme
s called lipase
s, EC 3.1.1.3, that use the catalytic triad of Aspartate (Asp), Histidine
(His), and Serine
(Ser) to hydrolyze long-chain triglycerides into partial glycerides and free fatty acids. The enzyme catalyzes the first reaction in the digestion of dietary lipid, with diglycerides being the primary reaction product. However, due to the unique characteristics of lingual lipase, including a pH optimum 4.5 -5.4 and its ability to catalyze reactions without bile salts, the lipolytic activity continues through to the stomach. Enzyme release is signaled by autonomic nervous system
after ingestion, at which time the serous glands
under the circumvallate and foliate papillae
on the surface of the tongue (see Figure 1)
secrete lingual lipase to the grooves of the circumvallate and foliate papillae. The hydrolysis
of the dietary fats is essential for fat absorption by the small intestine, as long chain triacyglycerides cannot be absorbed, and as much as 30% of fat is hydrolyzed within 1 to 20 minutes of ingestion by lingual lipase alone.
Lingual lipase uses a catalytic triad consisting of Aspartatic Acid-203 (Asp), Histidine-257 (His), and Serine-144 (Ser), to initiate the hydrolysis
of a triglyceride into a diacyglyceride and a free fatty acid. First, there is a series of deprotonation
s that make the serine a better nucleophile
. The lone pair
on the oxygen of the serine then undergoes a nucleophilic addition
to either the first or the third carbonyl
of the triacylglycerol. Next, the electrons that had moved to form the carbonyl transfer back down to reform the carbonyl. Then the diacyclglycerol leaving group is protonated by His-257. Following another round of deprotonations, the lone pair on the oxygen of water undergoes a nucleophilic addition to the carbonyl that reformed in the previous step. The electrons that had moved up from the carbonyl come back down to reform it and kick off the Ser, which again induces the chain of deprotonation. The final products of the reaction are the conserved catalytic triad, a diacylglycerol and a free fatty acid. Monoacylglyceride is also present in a lower concentration and is produced following a second round of hydrolysis by the same mechanism. It acts on tryglicerides to help breakdown food as a part of saliva composition.
(CF) have an 85% chance of additionally experiencing the effects of exocrine pancreatic insufficiency
. In the most extreme cases, these patients will produce no pancreatic lipase
, yet even when the enzyme is completely absent, dietary fat is still absorbed. Studies have shown that even in these cases, lingual lipase is present in normal amounts, and contributes to greater than 90% of total lipase activity in duodenum
. This can be attributed to the fact that lingual lipase has a low pH optimum and can thus remain active through the stomach into the duodenum, where there is a low pH
in patients with CF. It has, thus, been proposed that a possible treatment option for exocrine pancreatic insufficiency would be enzyme replacement therapy
using lingual lipase, increasing the amount of dietary fat absorption and decreasing the risk of malnutrition
. The proposed mechanism of lingual lipase preferentially cleaving short and medium chain triacylglycerols provides a means for absorption without the need for micelle formation and chylomicrons. Short and medium chain free fatty acids can be absorbed directly through the mucosal cells into the blood stream without further packaging and hence play a crucial role in nutrition for CF patients (and neonates).
, the fetus
is dependent on a high-carbohydrate
diet, and lingual as well as gastric lipases are present in the fetus from 26 weeks of gestation on. After birth, fat in mother's milk or a milk substitute
becomes the major source of nutrition. Absorptive rates of dietary fat are much lower in neonates than in adults, 65-80% as compared to >95% respectively, which can be attributed to low pancreatic lipase activity. Furthermore, milk fat is not a good substrate for pancreatic lipase. This fact, in combination with the bile salt deficiency and low pH throughout the gastrointestinal tract
of the neonate, demands that lingual lipase be the main enzyme catalyzing the hydrolysis of dietary fat. This enzyme activity has been seen as early as 26 weeks gestational age
, with ability to hydrolyze dietary fats variable according to digestive tract maturity.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s called lipase
Lipase
A lipase is an enzyme that catalyzes the formation or cleavage of fats . Lipases are a subclass of the esterases.Lipases perform essential roles in the digestion, transport and processing of dietary lipids in most, if not all, living organisms...
s, EC 3.1.1.3, that use the catalytic triad of Aspartate (Asp), Histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
(His), and Serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
(Ser) to hydrolyze long-chain triglycerides into partial glycerides and free fatty acids. The enzyme catalyzes the first reaction in the digestion of dietary lipid, with diglycerides being the primary reaction product. However, due to the unique characteristics of lingual lipase, including a pH optimum 4.5 -5.4 and its ability to catalyze reactions without bile salts, the lipolytic activity continues through to the stomach. Enzyme release is signaled by autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
after ingestion, at which time the serous glands
Serous glands
Serous glands contain serous acini, a grouping of serous cells that secrete a fluid, isotonic with blood plasma, that contains enzymes such as alpha amylase....
under the circumvallate and foliate papillae
Foliate papillae
Taste-buds, the end-organs of the gustatory sense, are scattered over the mucous membrane of the mouth and tongue at irregular intervals. They occur especially in the sides of the vallate papillae. There is a localized area at the side of the base of the tongue, the foliate papillae, in which they...
on the surface of the tongue (see Figure 1)
secrete lingual lipase to the grooves of the circumvallate and foliate papillae. The hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of the dietary fats is essential for fat absorption by the small intestine, as long chain triacyglycerides cannot be absorbed, and as much as 30% of fat is hydrolyzed within 1 to 20 minutes of ingestion by lingual lipase alone.
Proposed mechanism
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of a triglyceride into a diacyglyceride and a free fatty acid. First, there is a series of deprotonation
Deprotonation
Deprotonation is the removal of a proton from a molecule, forming the conjugate base.The relative ability of a molecule to give up a proton is measured by its pKa value. A low pKa value indicates that the compound is acidic and will easily give up its proton to a base...
s that make the serine a better nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
. The lone pair
Lone pair
In chemistry, a lone pair is a valence electron pair without bonding or sharing with other atoms. They are found in the outermost electron shell of an atom, so lone pairs are a subset of a molecule's valence electrons...
on the oxygen of the serine then undergoes a nucleophilic addition
Nucleophilic addition
In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....
to either the first or the third carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
of the triacylglycerol. Next, the electrons that had moved to form the carbonyl transfer back down to reform the carbonyl. Then the diacyclglycerol leaving group is protonated by His-257. Following another round of deprotonations, the lone pair on the oxygen of water undergoes a nucleophilic addition to the carbonyl that reformed in the previous step. The electrons that had moved up from the carbonyl come back down to reform it and kick off the Ser, which again induces the chain of deprotonation. The final products of the reaction are the conserved catalytic triad, a diacylglycerol and a free fatty acid. Monoacylglyceride is also present in a lower concentration and is produced following a second round of hydrolysis by the same mechanism. It acts on tryglicerides to help breakdown food as a part of saliva composition.
Lingual lipase and cystic fibrosis
Patients with cystic fibrosisCystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
(CF) have an 85% chance of additionally experiencing the effects of exocrine pancreatic insufficiency
Exocrine pancreatic insufficiency
Exocrine pancreatic insufficiency is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. This disease is found frequently in dogs. EPI is also found in humans afflicted with cystic fibrosis and Shwachman-Diamond Syndrome. EPI is caused by a progressive...
. In the most extreme cases, these patients will produce no pancreatic lipase
Pancreatic lipase
Pancreatic lipase, also known as pancreatic triacylglycerol lipase, is secreted from the pancreas, and is the primary lipase that hydrolyzes dietary fat molecules in the human digestive system, converting triglyceride substrates found in ingested oils to monoglycerides and free fatty acids.Bile...
, yet even when the enzyme is completely absent, dietary fat is still absorbed. Studies have shown that even in these cases, lingual lipase is present in normal amounts, and contributes to greater than 90% of total lipase activity in duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
. This can be attributed to the fact that lingual lipase has a low pH optimum and can thus remain active through the stomach into the duodenum, where there is a low pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
in patients with CF. It has, thus, been proposed that a possible treatment option for exocrine pancreatic insufficiency would be enzyme replacement therapy
Enzyme replacement therapy
Enzyme replacement therapy is a medical treatment replacing an enzyme in patients in whom that particular enzyme is deficient or absent. Usually this is done by giving the patient an intravenous infusion containing the enzyme...
using lingual lipase, increasing the amount of dietary fat absorption and decreasing the risk of malnutrition
Malnutrition
Malnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....
. The proposed mechanism of lingual lipase preferentially cleaving short and medium chain triacylglycerols provides a means for absorption without the need for micelle formation and chylomicrons. Short and medium chain free fatty acids can be absorbed directly through the mucosal cells into the blood stream without further packaging and hence play a crucial role in nutrition for CF patients (and neonates).
Fat digestion in neonates
In the uterusUterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
, the fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
is dependent on a high-carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
diet, and lingual as well as gastric lipases are present in the fetus from 26 weeks of gestation on. After birth, fat in mother's milk or a milk substitute
Milk substitute
A milk substitute is a liquid that replaces milk in a diet or recipe. This overlaps with but is distinct from the group of milk-like liquids called "milks" because of their similarity to the liquid produced by mammary glands....
becomes the major source of nutrition. Absorptive rates of dietary fat are much lower in neonates than in adults, 65-80% as compared to >95% respectively, which can be attributed to low pancreatic lipase activity. Furthermore, milk fat is not a good substrate for pancreatic lipase. This fact, in combination with the bile salt deficiency and low pH throughout the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
of the neonate, demands that lingual lipase be the main enzyme catalyzing the hydrolysis of dietary fat. This enzyme activity has been seen as early as 26 weeks gestational age
Gestational age
Gestational age relates to the age of an embryo or fetus . There is some ambiguity in how it is defined:*In embryology, gestational age is the time elapsed since conception. This interval is also termed fertilisation age....
, with ability to hydrolyze dietary fats variable according to digestive tract maturity.