Serine sphingosines

Phosphatidylcholine (l Ethanolamine CDP-ethanolamine Phosphatidylethanolamine (l Palmitoyl CoA Phosphatidylserine Sphingosine Serine... 

Phospholipids General structure of a phospholipid PHOSPHOLIPIDS (p. 199) Phospholipids are polar, ionic compounds composed of an alcohol (for example, choline, ethanolamine, serine, and glycerol) attached by a phosphodiester bridge to either diacyl-glycerol or to sphingosine. 

L-Serine gives rise to many other substances (Fig. 24-20) including sphingosine and the phosphatides. In many bacteria conversion to... 

Apart from PKA, some other protein-kinases were found to be controlled by forskolin, such as cytosolic sphingosine kinase in rat periosteal cells [186] and protein kinase B (PKB) [187]. The latter was found to be stimulated by the activation of PKA through a PI3 (phosphatidylinositol 3)-kinase-independent pathway. Furthermore, a distinct activation mechanism was suspected, other than that normally observed by growth factors such as insulin, since substitution of the serine at the S473 position of PKB with alanine could not prevent activation by forskolin. The JAK family of protein kinases in T lymphocytes can also be regulated by forskolin through the activation of PKA [188]. Thus it seems obvious that many other enzymes could be susceptible to control by forskolin. 

As discussed above, altering the stereochemistry of the sphingosine backbone has produced, in many instances, stereoisomers with altered bioactivity compared with the natural stereoisomer, for example, in activating the catalytic subunit of serine-threonine protein phosphatase 2A (63) or in inhibiting mitochondrial ceramidase (69). 

HPR-mediated leukemia cell c)4otoxicity is triggered by ceramide-induced mitochondrial oxidative stress and is regulated downstream by Bcl-2. Free Radical Res. 2007 41 591-601. Wang H, Maurer BJ, Reynolds CP, Cabot MC. N-(4-Hydroxyphenyl)retinamide elevates ceramide in neuroblastoma cell lines by coordinate activation of serine palmitoyltransferase and ceramide synthase. Cancer Res. 2001 61 5102-5105. Bandhuvula P, Tam YY, Oskouian B, Saba JD. The immune modulator FTY720 inhibits sphingosine-1-phosphate lyase activity. J. Biol. Chem. 2005 280 33697-33700. 

Fig. 4.5. Sphingo s Curio Shop. The coat rack in this case is the 3-carbon serine molecule, rather than glycerol. Fatty acids may attach just to the top carbon (sphingosine), or to both the top and middle carbons (ceramide). When, in addition, other groups attach to the lower carbon, one may get sphingomyelin (phosphocholine attaches), cerebrosides (single glucose or galactose attach), or gangliosides (oligosaccharide with sialic acid attach).

Purines and pyrimidines are derived largely from amino acids. The biosynthesis of these precursors of DNA, RNA, and numerous coenzymes will be discussed in detail in Chapter 25. The reactive terminus of sphingosine, an intermediate in the synthesis of sphingolipids, comes from serine. Histamine, a potent vasodilator, is derived from histidine by decarboxylation. Tyrosine is a precursor of the hormones thyroxine (tetraiodothyronine) and epinephrine and of melanin, a complex polymeric pigment. The neurotransmitter serotonin (5-hydroxytryptamine) and the nicotinamide ring of NAD + are synthesized from tryptophan. Let us now consider in more detail three particularly important biochemicals derived from amino acids. 

Ketiospbinganlne (KS) synthclasc Sphingosine synthesis palmLtoy 1-CoA + serine KS+CQj... 

Ketosphinganine (JS) synthetase Sphingosine synthesis palmitoyl-CoA + serine - KS + C02... 

C. Palmitoyl CoA and serine react to form a precursor that is converted to sphingosine. Sphingosine does not contain a glycerol moiety. Formation of an amide with a fatty acyl CoA converts sphingosine to ceramide. Ceramide may be converted to sphingomyelin, cerebrosides, and gangliosides. 

Sphingosine, which is used for the synthesis of sphingolipids, is produced from serine and palmitoyl CoA. 

The initial step in sphingosine formation involves the condensation of palmitoyl CoA with serine, which undergoes a simultaneous decarboxylation. 

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