Lysosomes are membrane enclosed organelles that contain over 50 different degradative enzymes. These enzymes are capable of breaking down an array of biological molecules such as proteins, lipids, and carbohydrates through the process of hydrolysis. Lysosomes are surrounded by a single membrane that keeps the hydrolytic enzymes inside the lysosome and prevents release of the harsh digestive enzymes into the cell. Lysosomes are considered to be the cell's 'digestive system' and are essential to the degradation of intracellular material. The lysosomal enzymes are all acid hydrolases which are only active at the acidic pH of lysosomes, but is not present in the cytoplasm. This, in conjunction with the membrane barrier, prevents the enzymes from acting on organelles outside of the lysosome, and thus prevents from uncontrolled digestion of the contents of the cytosol.
Lysosomes are responsible for recycling of the cells organic waste material. The lysosomal enzymes degrade the organic waste into small, simple molecules which can be utilised by the cell. This degradation process is called autophagy which refers to the fact that the cell is able to self-degrade its waste. The recycling process begins when phagosomes engulf the material to be degraded, and these phagosomes then transport the waste to the lysosomes. The phagosomes are produced by a splitting off of the ER membrane, which then surrounds the waste, engulfing it inside the phagocytic vesicle. This phagocytic vesicle then fuses with the lysosome, releasing the waste into the lysosome, allowing for degradation. This recycling process ensures that the cell remains healthy and prevents unnecessary energy expenditure in producing new organic products.
The digestive enzymes found in lysosomes such as glycosidases and proteases are synthesised in the endoplasmic reticulum (ER) of the cell. They are then transported to the Golgi apparatus, where they are modified and tagged in order for them to reach the lysosomes. This tagging involves the addition of mannose-6-phosphate. This mannose acts like a postcode label for the lysosomal enzymes which ensures that the transport system transports the enzymes to the correct location; - the lysosome. The enzymes all function in a similar way, in that they all catalyse a hydrolytic reaction which breaks bonds between molecules.
Examples of some of the main lysosomal enzymes:
Lysosomal enzymes are synthesized on membrane-bound organelles in the endoplasmic reticulum. The synthesised enzymatic proteins have a hydrophobic amino terminal signal sequence which is able to interact with a complementary signal recognition particle which initiates the transport of the lysosomal enzyme.
The enzyme is transported to the Golgi body where they undergo a number of post-translational modifications which ensure that the enzymes are sorted correctly in order for them to be transported to their ultimate lysosomal destination. The most critical modification that occurs to all lysosomal enzymes is the addition of a mannose-6-phosphate tag. This tag acts as an important recognition marker which can strongly bind, primarily by protein-protein interactions, to mannose-6-phosphate receptors. This leads to the proper transport of the lysosomal enzymes.
In some cases the lysosomal enzymes are inappropriately released into the cytoplasm. These enzymes are sometimes able to bind to mannose-6-phosphate receptors which are present on the cell surface of transportation vesicles and can then be internalised and properly transported. Sometimes however, this doesn't occur and the enzymes are broken down by lysosomes already present in the cytoplasm.
The targeting of lysosomal enzymes from their site of synthesis in the endoplasmic reticulum to their final destination - the lysosomes - occurs as a result of, and is directed by, a number of protein and carbohydrate recognition signals on the enzymes. These signals can interact with other proteins and organelles which faciliates correct transport of the lysosomal enzymes.
Mannose-6-phosphate is a key targeting signal for the hydrolytic lysosomal enzymes. The mannose tag is added to the acid hydrolase precursor proteins in the Golgi apparatus in order for them to reach the lysosome. The addition of the mannose tag occurs specifically in a reaction that involves uridine diphosphate (UDP) and N-acetylglucosamine (NAG). The tagged proteins are recognised and bound by mannose-6-phosphate receptor proteins which are found in the Golgi apparatus. From the Golgi apparatus the tagged proteins are transported via vesicles to late endosomes. The pH in the late endosomes is slightly acidic at pH 6; this pH causes the mannose-6-phosphate to dissociate from the receptor protein, and ultimately results in the release of the lysosomal enzymes. These lysosomal enzymes are then transported to their final destination - the lysosomes. The mannose-6-phosphate receptor proteins are packaged into vesicles and are transported back to the Golgi-body for recycling.
A malfunction or absence of one of the 30 lysosomal enzymes results in a lysosomal storage disease. Many of these diseases are due to a failure to synthesise an active form of the relevant enzyme, however some of the diseases occur as a result of an inability to transport the enzymes to the required location.
An example of one such lysosomal storage disease is Pompe's disease. This is a glycogen storage disease which causes breathing problems and heart defects. It is an inherited disorder that is caused by the lack of the enzyme hydrolase acid alpha glucosidase (GAA) that is contained in lysosomes. GAA is responsible for breaking down glycogen to glucose. If GAA is malfunctioning then glycogen builds up in the body, specifically causing damage to the muscle cells.
Inclusion cell disease or I-cell disease is another lysosomal storage disease. However, unlike the other diseases discussed, this condition is caused by the failure to tag, by phosphorylation, all of the hydrolytic lysosomal enzymes with mannose-6-phosphate. This malfunction means that instead of the enzymes being transported to the lysosome, they are instead secreted from the cell.
The packaging and transport of lysosomal enzymes has been studied extensively, and a number of studies have been conducted on people with malfunctions in the transport systems of lysosomal enzymes. It is through such studies that the complex sorting process has been better understood, and as such it has become possible to understand where targeting has gone array in those individuals with I-cell disease.
Lysosomes are membrane enclosed organelles that contain over 40 different hydrolytic enzymes. These organelles are responsible for the break down or hydrolysis of cell components and waste products. Lysosomes are therefore essential to cell functioning and general health. If there is a malfunction with the lysosome, in terms of its synthesis, the synthesis of the hydrolytic enzymes inside or with the transport of its products a lysosomal storage disease can occur, and such diseases can be life threatening.
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