Biosynthesis Of Sphingolipids And Associated Defects

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From single celled to complexly organized organisms, the overall survivability of any organism is dependent on a series of complex and highly regulated chemical reactions. Metabolism is any set of chemical reactions that are localized within prokaryotic or eukaryotic cell types 9. Metabolic reactions influence several aspects of an organism's well-being; including growth, reproduction, maintenance of cellular structures, and provide the ability to respond and adapt to an ever changing environment 9. Within the scope of metabolic reactions; two types of reactions can be described, anabolic and catabolic metabolic reactions 9. Anabolic reactions are a series of chemical reactions that utilize the input of energy to rearrange monomers, or simple building blocks, into larger more complex molecules, or polymers 9. Examples of anabolic metabolic reactions include gluconeogenesis, lipid synthesis, and protein synthesis. Catabolic reactions are metabolic reactions that breakdown various polymers into monomers, releasing energy that can be utilized for other cellular functions 9. Examples of catabolic reactions include Glycolysis, Citric Acid Cycle (CAC), and glycogen degradation. Found in every metabolic reaction there are regulatory molecules known as enzymes. Enzymes have the ability to increase or decrease the rate of the reactions they are acting on 9. This is achieved by lowering the activation energy for a reaction 9. Through the use of various enzymes acting on the numerous macromolecules transported into the cell, essential molecules are synthesized to allow basic cellular function to continue.

Lipid synthesis is an anabolic process that is essential to a variety of biological systems. Lipid synthesis provides several functions including an efficient source of fuel reserves, aids in extra-cellular signaling molecules, and serve as an essential component of cellular membranes 9,10,7. Focusing on the synthesis of cellular membranes components, which are comprised of phospholipids and sphingolipids, a complex set of biochemical reactions must take place in order to properly synthesize these lipid molecules 9,10,7. These sets of reactions are also highly regulated by a variety of enzymes to ensure the proper products are made 9,10. Recently, a greater understanding of the synthesis of sphingolipids, and the effects of improper manufacturing of these complex molecules within biological system have been obtained. By understanding the biosynthesis of sphingolipids, the treatment and prevention of a variety of illnesses and diseases would vastly improve.

Sphingolipid Biosynthesis Pathway

Figure 1.1 - Structure of Sphingolipids The lipids that are considered to be cellular membrane components are phospholipids and sphingolipids 7,8,9,10. Phospholipids are molecules composed of a glycerol backbone and 2 fatty acid chains; whereas, sphingolipids are composed of sphinogosine backbone and a number of fatty acid chains 7,8,9,10. The two most common places that sphingolipids are found in the plasma membrane of all eukaryotic cells and, in highest concentration, in cells comprising the nervous system (BOOK). Sphingolipids can be subdivided into three categories: (1) sphingomyelin, (2) cerebroside, and (3) gangliosides 7,8,9,10. Sphingomyelin functions in myelin sheath portions of nerve cells (BOOK). The substituent for sphingomyelin is phosphorylcholine. Cerebroside also functions as a primary component of myelin. The difference between sphingomyelin and cerebroside is that cerebroside has a substituent group consisting of glucose or galactose 8,9. Finally, gangliosides function in binding-immune system cell to an induced inflammatory response and are found in highest concentration in the nervous system. Gangliosides make up much of the gray matter found throughout nervous tissue, and are up to 6% of the lipids 3,4,9. Ganglioside is an oligosaccharide that has a salic acid attached to the terminal hydroxyl group 3,4,9. These molecules are produced through a series of relatively simple number of reactions.

The precursor for the synthesis of sphingolipids is palmitoyl CoA 3,4,9. Palmitoyl CoA is accompanied by the addition of serine residue, which are the first reactants needed to produce a sphingolipid 3,4,9. Through a condensation reaction, hydrogen cation produces 3-ketosphinganine.

Figure 2.1 - Preparation of Sphingosine

This step of the reaction also cleaves carbon dioxide (COâ‚‚) and CoA 3,9. With 3-ketosphinganine now produced, this molecules interacts with nicotinamide adenine dinucleotide phosphate (NADPH + H+) and is reduced to yield NADP+ and dihydrosphinosine 3,9. Dihydrosphinosine is then converted into ceramide through the acyelation of a long-chain acyl CoA to the amino group of dihydrosphinosine 3,9. The final step in the formation of ceramide is an oxidation reaction that completes the trans double bond 3,9. Once ceramide is completely formed that are two directions for the reaction to proceed. To produce sphingomyelin, ceramide interacts with phosphatidylcholine, which cleaves a diacylglycerol (DAG) to produce the final molecule 3,9. Ceramide can also interact with uridine diphosphate (UDP) bound to glucose. The reaction binds that glucose molecule to ceramide, and yields cerebroside 3,9. The addition of additional activated sugars to cerebroside produces gangliosides 3,9. Refer to illustration 2.1 - Preparation of Sphingosine, to obtain visual representation of the how the various molecules are altered to obtain sphingosine. The following figure, figure 3.1 - Production of Various Sphingolipids, further illustrates the alterations made to sphingosine to produce the metabolic precursor, ceramide and subsequent sphingolipid molecules such as gangliosides.

Figure 3.1 - Production of Various Sphingolipids

Prokaryotic vs. Eukaryotic Uses for Sphingolipids

As previously mentioned, there are a variety of uses that sphingolipids serve in eukaryotic cell types. The prevalence of sphingolipids found throughout the nervous system of mammalian species, specifically humans, cannot be overlooked. Because nervous tissue contains such an increased amount of these lipid molecules, proper understanding of how these molecules are synthesized and degraded can provide additional insight in the treatment of several diseases, including Tay-Sach's disease and respiratory distress syndrome. Additionally, the formation of ceramide may serve as an adequate second messenger, resulting in programmed cell death or apoptosis in some cell types 5. The prevalence of sphingolipids in prokaryotes is not as pronounced as in eukaryotic cellular systems. Overall, sphingolipids are considered to be never rare in prokaryotes 5. The use of sphingolipids are characteristic of some types of prokaryotic bacteria. The member of the Bacteroides genus do, however, synthesis sphingolipids 5. Variations of the sphingolipid molecule made, they include the addition of phosphorylethanolamine, phosphorylglycerol, and to a significantly decreased degree, phosphorylglycerophosphate. All of these addition are esterified to ceramide (N-acylsphingosine) 5.

Defects in Pathway and Associated Disease States

Lipid storage disorders refer a class of disease states that lack the hydrolytic enzymes to effectively remove the sugar residues for the sphingolipids (CITE). The following table, Table 1.1 - Lipid Storage Disorders and Associated Defective Enzyme, show the various diseased states and the defective enzyme associated with each state (CITE).

Disease State

Enzyme Deficiency


α-galactosidase A



Niemann - Pick Type A and B

Acid sphingomyelinase

Niemann - Pick Type C





β-hexosaminidase A and B


β-hexosaminidase A

GM1 - gangliosidosis


Metachromatic leukodystrophy

Arylsulphatase A

Table 1.1 - Lipid Storage Disorders and Associated Defective Enzyme 4

All of the disease states associated with improper lipid storage can be attributed to acquisition of a faulty gene, which has been passed on through the parent generation to the offspring generation . Fabry disease is a rare disease caused by the acquisition of X-linked recessive lysosomal storage gene. Some of the symptoms associated with this Fabry disease include complications with renal processes, cardiac complications due to glycolipid build-up, and clouding of the corneas 1,2,6,8. Gaucher's disease, which is the most common the lipid storage diseases, is characterized by the build of glycolipids in leukocytes (WBCs). Symptoms that accompany this disease include liver, spleen, brain, and lungs. Anemia, skin discoloration, and low platelet count are also common symptoms of this condition 1,2,6,8. Niemann - Pick Type A,B, & C are also genetically inheritable diseases, and characterized by the accumulation of sphingomyelin in the central nervous system, causing slurred speech, abnormal posturing of limbs, and in severe cases, gradual loss of intelligence 1,2,6,8. Krabbe disease is an autosomal recessive disease that effects the myelin sheath covering the axons of nerve cells 1,2,6,8. The symptoms of Krabbe disease include seizures, slow mental development, slow motor development, and blindness (CITE). Sandhoff disease is medical equivalent to Tay-Sach's disease 1,2,6,8. Metachromatic leukodystrophy (MLD) effects the central nervous system as well. Symptoms of this disease include convulsions, dementia, and paralysis 1,2,6,8.

Among the numerous lipid storage disorders, Tay-Sach's disease can be considered the most well-known. Tay-Sach's disease is an autosomal recessive disorder and, generally, results in dead by the age of 4 1,4,9,11. On a cellular level, the massive accumulation of a specific ganglioside, GMâ‚‚, in the central and peripheral nervous system; results in rapid degradation of the majority of mental and motor function 1,4,9,11. From the time of birth, up to around six months, infants will develop normally 1,4,9,11. Generally, around the six months of life, the early symptoms of Tay-Sach's will manifest. Early onset symptoms include regression in grasping, loss of interest, and increase sensitivity to noises 1,4,9,11. Within the first 12 to 18 months of life, blindness progresses, muscular wasting increases, and feeding becomes a problem 1,4,9,11. Often during the second phase of Tay-Sach's is accompanied with convulsions and seizures due to the increased build up of gangliosides throughout the nervous system 1,4,9,11. The final phase of Tay-Sach's yields a completely immobile child, in addition to enlargement of the head; which is also due to the build of gangliosides within the nervous system 1,4,9,11.

From a biochemical standpoint, the accumulation of the specific ganglioside, GM₂, is a direct result of a faulty enzyme used to break down the toxic version of the molecule. In a properly function degradation reaction of the ganglioside molecule, the N-acetylgalactosamine residue is removed by the enzyme known as β - N - acetylgalactosaminidase 4,6,8,9. The following illustration, figure 4.1 - Enzymatic Activity of β -N -acetylgalactosaminidase, provides further insight to the enzyme activity.

Figure 4.1 - Enzymatic Activity of Beta-N-Acetylgalactosaminidase

Unfortunately, the progression of Tay-Sach's disease is inevitable. An individual with this condition has a very limited quality of life, for a very short time. One way to combat the prevalence or manage the situation that parents are put in, when dealing with the chance of Tay-Sach's, is undergoing the proper genetic testing to see if both parents are carriers for this autosomal recessive disorder.

Disease Prevalence and Treatment

Figure 5.1 - Genetic Combination of Autosomal Recessive Disorders Awareness seems to always be the best line of defense when dealing with the numerous lipid storage diseases. Because of the overall nature and rapid manifestations of symptoms exhibited in individuals with these disorders, parents often have difficult choices to make. One way to minimize the effect of Tay-Sach's, not only on the parents of offspring but the offspring themselves is to have hexoaminidase assays performed 1,2,4,11. Through the testing of various cellular components of a person wanting to know if he/she is a carrier of Tay-Sach's, for example blood serum, WBCs, and skin fibroblasts, This fact is even more important in the Jewish community, which 1 of every 27 jews are carriers for Tay-Sach's disease 1,2,4,11. Additionally, other groups of French Canadians and Cajun community living around the Louisiana area, seem to have a slightly diminished prevalence of around 1 out of every 30 persons 1,2,4,11. The prevalence of the number of people that are carriers greatly increase in people among these community when compared that of non-Jewish and Cajun roots are compared to the prevalence of the Tay-Sach's gene in the general public 1,2,4,11. Although, it should be noted that individuals of Irish decent have a 1 in 50 chance to be a carrier of the Tay-Sach's disease 1,2,4,11. By implementing the proper genetic testing, over the past 25 years, the reduction of children that are born with Tay-Sach's has been reduced 1,2,4,11. More often than not, children being born with Tay-Sach's are a part of couples that were not originally considered to have an increase risk of passing on this disease 1,2,4,11. If conception is already achieve; however, testing for Tay-Sach's can still be done through two process amniocentesis and chronic villus sampling (CITE). Amniocentesis is performed between the 15th and 16th week of pregnancy 1,2,4,11. By inserting a needle in the uterine cavity, amnion is withdrawn and various genetic test can be run 1,2,4,11. Chronic villus sampling is run earlier than that of amniocentesis, between the 10th and 12th week of pregnancy 1,2,4,11. This procedure focuses on the sampling of cell drawn from the placenta, at which point various genetic tests can be ran 1,2,4,11. These tests provide information, which mainly affects the decision process of the parents yielding new offspring. Without adequate treatment options for those that currently have Tay-Sach's disease, abortion of the fetus is often a decision that is made.


Tay-Sach's is a debilitating disease that cripples the central and peripheral nervous system of infant children. Because of the rapid nature and progression of this disease, treatment and/or management of symptoms is delayed and non-existent, but to the time is takes to manifest within the individual that the disorder is affecting. It is hard to imagine that a small enzyme, which is responsible for the degradation of the gangliosides, is responsible for this disease. Without adequate testing and screening, it seems that Tay-Sach's will always force good people to make hard decision about their offspring. Although, with advances in the gene therapy and implantation of the known enzyme; treatment for Tay-Sach's is becoming more, and more of a possibility. This gives hundreds of children a fighting chance in the struggle to experience life the way many people get on a daily basis. The importance of understanding of how biochemical pathway behaves and the factors that affect the overall behavior of the pathway cannot be understated. Through the progression and administration of the knowledge obtained, again, the general public pose a serious threat to Tay-Sach's.