Sphingolipid Catabolism: Comparison
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In the plasma membrane and other cellular compartments (endosome/lysosome), sphingomyelin can be hydrolyzed to ceramide by sphingomyelinases.  Ceramide generated by this pathway is further degraded into sphingosine by ceramidases.  Shingosine can also be phosphorylated by sphingosine kinases to sphingosine-1-phosphate. Changes in the profiles of sphingomyelin and its metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P) can result in a pathological condition triggered by accumulation or by altering cell signaling.

  • diabetes
  • angiotensin II-induced hypertension
  • sphingomyelin

1. Introduction

1. Introduction

1.1. Sphingolipid Metabolism

In thNume anabrolic pathway, sphingolipids synthesis begins in the endoplasmic reticulum with the condensation of L-serine and palmitoyl coenzyme A (CoA) to form 3-ketous human studies have shown that, in cardiovascular, renal, and metabolic diseases, the profiles of sphinganineomyelin [1][2][3][4] byand serine palmitoyltransferase.its metabolites ceramide Subsequently[5][6][7][8][9][10][11], 3-ketosphinganosine reduct[12], ase is responsible for reducing 3-ketod sphinganine to sphinganine,osine-1-phosphate (S1P) which[13][14] can be acylated to form dihydroceramide by ceramide synthase. Finally, dihydroceramide is oxidized by a desaturase, which results in ceramide formationre altered (reduction or elevation) in the plasma, organs (liver and heart), and tissues (skeletal muscle and [1][2][3]. Ceramide is transported from the endoplasmic reticulum to the Golgi apparatus and is converted into sphingomyelin by sphingomyelin synthase or glycosphingolipids byipose). Most of these studies focused on the determination of ceramide glucosyltransferasa. Sphingomyelin and complex glycosphingolipids can be transported to the plasma membrane (Figure 1) [3][4].

Iin plasma. However, it is necessary to perform preclinical the plasma membrane and other cell compartments, thestudies to determine the content of sphingomyelin can be hydrolyzed by sphingomyelinases (SMases) and release ceramide.  Ceramide can be hydrolyzed by ceramidases (CDases) to form sphingosine, which can be phosphorylated by sphingosine kinase (SK) to generateand its bioactive metabolites in plasma and organs such as the brain, liver, heart, and kidney, because the sphingosine-1-phosphate (S1P) (Figure 1) [3][5][6][7][8][9]. S1P clipid metabolism imbalan bce cleavaged by the S1P lyase to a fatty aldehyde and phosphoethanolaminean be affected directly [10].or Alterinatively, S1P can be dephosphorylateddirectly in various organs.

On back to sphingosine by phosphataseshe other [11]. S1P chand, act as an intracellular second messenger or an extracellular ligand [12][13].

1.2. Classification of Sphingolipid Catabolism Enzymes

Accordchanges in the expression or activingty to the optimal pH for their activity, SMases are classified into acid, neutral, and alkaline. aSMase can be subclassified based oof the enzymes that participate in sphingolipid metabolism may explain the alterations in their cellular locatioprofile.

In into lysosomal aSMase (L-SMase) and secretory aSMase (S-SMase) [5][6]. Ceramhe anabolic pathway, the synthesidases also have been classified according to their optimal pH in acid, neutral, and alkaline [7][8]. Tw of sphingolipids stars by the condensation of serine and palmitoyl-CoA isoforms of nto 3-ketosphingosine kinases (SKs) have been identified, sphingosine kinase-1 and sphingosine kinase-2anine by the enzyme serine palmitoyl transferase, [9].

1.3. Genetic Diseases of Sphingolipid Catabolism Enzymes

Types A and B Niemann Pick disease is causit is followed by aSMase deficiency, which leads to organ dysfunction due to the accumulation of reduction yielding sphinganine. The sphingomyelin in various organs. Niemann Pick disease is inherited as recessive traits [14]. Faanine is acylate by ceramide synthase resulting dihydrbocer disease is a lysosomal storage disorder, it is causamides. Finally, ceramide is formed by mutations in the gene that encodes to aCDase, which lead to decreased aCDase activity and in turn, to the dehydrogenation of dihydroceramide by dihydroceramide accumulation and various pathological manifestations. Farber disease is inheridesaturase. The ceramide is converted in an autosomal recessive manner [15].

1.4. Sphingolipid Catabolism Enzymes as Therapeutic Targets in Cardiovascular Diseases

Nuto sphingomyerous human studies have shown that, in cardiovascular, renal, and metabolic diseases, the profiles of lin by sphingomyelin synthase or glycosphingomyelin [16][17][18][19] anlipid its metabolitesy ceramide [20][21][22][23][24][25][26], sphingosine [27], and sphingosine-1-phosphate (S1P) [28][29] are altered (reduction or elevation) in the plasma, organs (liver and heart), and tissues (skeletal muscle and adipose). Most of these studies focused on the determination of ceramide in plasma. However, it is necessary to perform preclinical studies to determine the content of osyltransferase. In the catabolic pathway, sphingomyelinases (SMases) hydrolyzes sphingomyelin and its bioactive metabolites in plasma and organs such as the brain, liver, heart, and kidney, because theto release ceramide, which is hydrolyzed into sphingolipid metabolism imbalance can be affected directly or indirectly in various organs.

Csine and S1P by ceramidase (CDase) and sphainges in the expression or activity of the enzymes that participate in sphingolipid metabolism may explain theosine kinase (SK), respectively (Figure 1) alterations in their profile[15].

Concerning the expression at the mRNA level of the enzymes involved in the synthesis (serine palmitoyltransferase) and degradation of ceramide (SMase, CDase, and SK-1), the levels of these enzymes were increased in intra-abdominal adipose tissue and the myocardium of obese patients with or without type 2 diabetes [3016][3117].

Regarding enzyme activity, secretory SMase activity increased in the serum of patients with type 2 diabetes, chronic heart failure, or acute coronary syndromes [3218][3319][3420]. In the adipose tissue of obese non-diabetic or diabetic patients, the activity of serine palmitoyltransferase, neutral and acid CDase (nCDase and aCDase) was increased, while the aSMase activity was decreased [227].

Changes in the profiles of sphingomyelin and its metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P) can result in a pathological condition triggered by accumulation or by altering cell signaling.

In Therefore, drugs that modify the expression or activity of the enzymes involved in sphingolipid metabolism are attractive candidates for the treatment of cardiovascular, renal, and metabolic diseases.

Resea previous study, researchers evaluated the sphingomyelin content and its metabolites in two experimental models: diabetic and hypertensive rats. The results show that, in the plasma and liver emonstrated that in the isolated perfused rat kidney of diabetic rats, sphingomyelin is increased; in the heart, ceramide; and in the kidney, S1P. Moreover,the vasoconstriction produced by S1P increases [21]. Add sphitingomyelin was observed onally, in the plasma and all evaluated organs of hypertensive rats, as well as increased ceramide and sphingosine in the heart, and increased S1P in the plasma, kidney, and heart (Figure 2isolated perfused rat kidney, angiotensin II (Ang II).

The results suggest that empagliflozin downregulates the interaction of the de novo pathway and the catabolic pathway of sphingolipid metabolism in diabetes, whereas, in Ang II-dependent hypertension, it only downregulates the sphingolipid catabolic pathway timulates ceramide formation via the activation of nSMase (Figure 32) [22].

2. Applications

2.1. Pharmacologic Inhibitors of Sphingolipid Catabolism Enzymes

There use of pharmacologic inhibitors has been critical for the study offore, drugs that modify the expression or activity of the enzymes involved in sphingolipid cametabolism enzymes as a potential therapeutic approach in respiratory (chronic obstru are attractive pulmonary disease, idiopathic pulmonary fibrosis), neurodegenerative (Alzheimer’s disease), metabolic (obesity, diabetes), andcandidates for the treatment of cardiovascular disease (Table 1), renal, and [35][36][37][38].

          Table 1. Pharmacologic inhibitors of sphingolipid metabolism enzymes.

Enzyme

Pharmacologic inhibitors

aSMase

Tricyclic antidepressants (desipramine, imipramine, and amitriptyline), SMA-7, and siramesine.

nSMase

scyphostatin, GW4869, and G11AG

CDase

N-Oleoylethanolamide (NOE), D-e-MAPP, LCL84, LCL204, LCL464, SABRAC, DP24c, KPB70, KPB67, Ceranib-2, Carmofur, and 17a.

SK1

SKI-178, RB-005, PF-543, SLP7111228, Genzyme 51

SK2

(R)-FTY720-OMe, ABC294640, K145, SLP120701, SLR080811

2.2. Sphingosine 1-Phosphate and its Receptors as Drug Targets

Onme of the biological applications of S1P has emerged witabolic disease.

Th the discovery of the immunosuppressant drug.  FTY720 acts as an S1P agonist when it is phosphorylated to FTY720-P.  FTY720 can be phosphorylated by both SK1 and SK2, but SK2 has more affinity for the drug than SK1 [39]. FTY720-P results suggest that empagliflozis a potent agonist of four S1P receptors: S1P1, S1P3-5 [40][41].

2.3. Sphingomyelin and its Metabolites as Potential Therapeutic Targets of COVID-19 Disease

In the ser downregum of platients with COVID-19 increased the concentraes the interaction of serine palmitoyltransferase and acid sphingomyelinase (aSMase). Also, increased the concentration of dihydrosphingosine, dihydroceramide, ceramide, and sphingosine, and decrease sphingosine-1-phosphate [42][43]. Symptthe de novo pathway and the catabomatlic COVID-19 patients exhibited a decrease in their serum spathway of sphingosine levels compared to asymptomatic patients levels [44]. Inlipid metabolism in terestingly, sphingosine binds to angiotensin-converting enzyme 2 (ACE2) and prevents its interaction with the viral spike protein of SARS CoV 2 in human nasal epithelial cells [45]. Ie diabetes, whereas in Ang II-dependenfection of human epithelial cells and different human cell lines with SARS-CoV-2 is reduced by treatment with amitriptyline and other antidepressants. In addition, the administration of anticeramide antibodies or neutral ceramidase also protects against SARS-CoV-2 infections [46] hypertension, it only downregulates the sphingolipid catabolic pathway (Figure 2).

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