Sphingomyelinase - Essay Example

These enzymes have been categorized into six different classes namely Mg+ dependant neutral SMase, Mg+ independent neutral SMase, acid SMase, secretory SMase, and alkaline SMase and bacterial SMase (Goni and Alonso 38). This paper mainly discusses the mode of action and medical importance of neutral SMase. Two neutral SMase have been determined in mammals. Mg+ dependant nSMase 1 is concentrated in kidneys while Mg+ independent nSMase 2 is mostly present in golgi bodies of brain (Mizutani et al. 3727). In mammals, nSMase acts as an integral membrane protein whereas in bacteria they are soluble proteins.

They play an important role in the human body by catalyzing the production of ceramide and regulate a number of metabolic events such as cellular differentiation, arrest of cell cycle and apoptosis (Mizutani et al. 3727; Gallardo et al. 1305). The mechanism of nSMase has mostly been studied on the enzyme obtained from Bacillus Cereus. Their working has been described as a divalent metal-ion dependant manner (Ago et al. 16157). The enzyme obtained from the bacteria is quite similar to the mammalian nSMase in its action and function.

The active site of nSMase is comprised of a glutamic acid (Glu) residue and histidine (His) residue, both of which are bound to either one or two metal cations, usually Co+ or Mg+. These cations support the action of SMase by recruiting sphingomyelin towards the active site. The cation at the Glu residue acts on the region between C1 and the phosphate group of sphingomyelin by interacting with amido-oxygen and ester-oxygen. On the other hand the cation at the His residue combines with the oxygen atom of the phosphate group of sphingomyelin resulting in a stabilized phosphate group.

Furthermore this interaction activates a water molecule by lowering the value of acid dissociation constant of one of the bridged water molecules. This activation allows water molecule to attack the phosphate group of sphingomyelin as a nucleophile. Later the reformation of phosphate group in its tetrahedral shape results in the formation of the two products; ceramide and phosphorylcholine. One of the commonest of disease associated with sphingomyelinases is Niemann-Pick disease. An autosomal recessive lysosomal storage disease, it is caused due to mutation in either SMPD1 gene or NPC1 gene and is classified into three types; A, B and C.

Symptoms are characterized according to the organ of accumulation. This disorder occurs when there is deficiency of sphingomyelinases leading to a stop in the degradation pathway of lipids and resulting in accumulation of sphingomyelin within the lysosomes of affected cell causing them to become enlarged. This along with many small vacuoles renders a foamy appearance to the affected cell. Pharmacologically, there are no reported drugs which are synergistic in action to sphingomyelinases, although a number of researches have now appeared which discuss the inhibitors of sphingomyelinases (Canals, Perry, Jenkins and Hannun 694).

Scyphostatin, which is attained from the mycelia extracts of Trichopezia mollissima has emerged as a neutral sphingomyelinase inhibitor (Czarny and Schnitzer 1344). As ceramide is understood to be a second messenger molecule working like inflammatory mediators (TNF?, IL-1, IL-6 and LPS) it is believed that scyphostatin