Palmitoyl thioesterase

Palmitic acid Palmitoyl-thioesterase Soybean Down regulation Buhretal. (2002)... 

Infantile neuronal ceroid lipofuscinosis CNL1 Palmitoyl protein thioesterase Saposins... 

The neuronal ceroid lipofuscinoses (CLN), also referred to as Batten s disease, are a group of disorders characterized by the accumulation of autofluorescent lipopigments. Clinical hallmarks include blindness, seizures, cognitive and motor decline and early death. Age of onset varies from infancy to adulthood. Eight genetic forms have been identified [4]. Two involve lysosomal acid hydrolases. CLN1 codes for palmitoyl protein thioesterase 1. Clinically it presents most often in infancy and leads to loss of active movement and visual contact by 3 years of age. It is most common in Finland, where its incidence is 1 20,000. CLN2 codes for a lysosomal pepstatin-insensitive acid protease. 

Lukacs Z, Santavuori P, Keil A, Steinfeld R, Kohlschiitter A (2003) Rapid and simple assay for the determination of tripeptidyl peptidase and palmitoyl protein thioesterase activities in dried blood spots. Clin Chem 49 509-511... 

The thioesterase activity of the fatty acid synthase prefers the palmitoyl acyl carrier protein thioester as substrate. 

This first round of elongation produces the four-carbon butyryl-ACP. The cycle now repeats with malonyl-ACP adding two-carbon units in each cycle to the lengthening acyl-ACP chain. This continues until the 16-carbon palmitoyl-ACP is formed. This molecule is not accepted by the acyl-malonyl-ACP condensing enzyme, and so cannot be elongated further by this process. Instead it is hydrolyzed by a thioesterase to give palmitate and ACP. 

The cycle of transfer, elongation, reduction, dehydration, and reduction continues until palmitoyl-ACP is made. Then the thioesterase activity of the FAS complex releases the 16-carbon fatty acid palmi-tate from the FAS. 

Data from Verkruyse et al. (1997). Intracellular palmitoyl-protein thioesterase (PPT) was determined using whole cell lysates and anti-PPT antibody. PPT protein in the medium (extracellular) was detected following partial purification to enrich for PPT prior to immunoblotting with anti-PPT antibody. 

Terman A, Neuzil J, Kagedal K, et al. Decreased apoptotic response of inclusion-cell disease fibroblasts a consequence of lysosomal enzyme missorting Exp Cell Res 274 9-15,2002. Verkruyse LA, Natowicz MR, Hofmann SL Palmitoyl-protein thioesterase deficiency in fibroblasts of individuals with infantile neuronal ceroid lipofuscinosis and I-cell disease. Biochim Blophys Acta 1361 1-5,1997. von Figura K, Hasilik A Lysosomal enzymes mind their receptors. Anna Rev Biochem 55 167-193, 1986. 

Palmitoylated proteins Infantile neuronal ceroid lipofuscinosis (NCL) Palmitoyl-protein thioesterase lp32... 

Goswami, R., Ahmed, M., Kilkus, J., Han, T., Dawson, S. A., and Dawson, G. Differential regulation of ceramide in lipid-rich microdomains (rafts) Antagonistic role of palmitoyl -protein thioesterase and neutral sphingomyelinase 2. J Neurosci Res 81 (2005) 208-217. 

Of the deficits unrelated to the glycolipids which show an abundant clinical literature but less interest manifested by scientists in the field of lipidomics are ceroid lipofuscinosis (the deficiency in palmitoyl-protein thioesterase (PPT)) and the Sjogren-Larsson syndrome, a defect of ALDH3A2 gene which encodes fatty aldehyde dehydrogenase (FALDH). It is pertinent to question the reason for such differences between clinical and basic scientific interests reflected in literature citations. 

Ceroid Lipofucinosis palmitoyl-protein thioesterase (PPT 1) granular osmiophilic deposits of acylated proteins CNLl (for PPTl) CNLx>10 1 12500 fluorimetric enzyme assay of PPT... 

The condition is caused by deficiencies of palmitoyl protein thioesterase 1 (PPTl) (or tripeptidyl peptidase 1 (TPPl) and possibly other enzymes resulting in the same clinical presentation of NCL (for Aeural Ceroid Lipofuscinose)). PPTl cleaves long-chain fatty acids from S-acylated proteins within the lyso-some (Lu et al., 1996). How the loss of this activity causes the death of central nervous system neurons is not known. 

The two subtypes of NCLs are due to deficiencies either in the palmitoyl protein thioesterase 1 (PPTl) protein or in the tripeptidyl peptidase 1 (TPPl) protein. The trial aforementioned by a cell therapy was comprised of neural stem/progenitor cells which constitutively synthesize and secrete both the PPTl and TPPl enzymes. In culture, these secreted enzymes are internalized by... 

Lu J.Y., Verkruyse L.A., Hofmann S.L., Lipid thioesters derived from acylated proteins accumulate in infantile neuronal ceroid lipofuscinosis correction of the defect in lymphoblasts by recombinant palmitoyl-protein thioesterase. Proceedings of the National Academy of Sciences of the United States of America 93 (1996) 10046-10050. 

Young E.P., Worthington V.C., Jackson M., Winchester B.G., Pre- and postnatal diagnosis of patients with CLNl and CLN2 by assay of palmitoyl-protein thioesterase and tripeptidyl-peptidase I activities, European Journal of Paediatric Neurology 5 Suppl A (2001) 193-196. 

Two thioacyl protein thioesterases (APTs) have been identified. Unlike PATs, both are soluble proteins. Acylprotein thioesterase-1 (APTl) was purified from rat liver cytosol using palmitoylated G-protein a-subunit as a substrate (J.A. Duncan, 1998, 2002). This thioesterase, a 29-kDa monomeric protein, is likely to be the one involved in turnover of cytoplasmically disposed thioacyl groups of proteins. It displays both acylprotein thioesterase activity as well as lysophospholipase activity, but thioacylproteins are by far the preferred substrates. The second acylprotein thioesterase, protein palmitoylthioesterase-1 (L.A. Camp,... 

Fig. 4. Palmitoylation-dependent trafficking of Ras (redrawn from Ref. [13]). Famesylated Ras weakly associates with Golgi membranes but is kinetically trapped once it is S-acylated (straight lines). S-acylated, famesylated Ras is transported to the plasma membrane (PM) via secretory vesicles. At the PM, a thioesterase depalmitoylates Ras, releasing the protein and allowing it to reassociate with the Golgi.

Jones, A., Davies, H.M., Voelker, T.A. 1995. Palmitoyl-acyl carrier protein (ACP) thioesterase and the evolutionary origin of plant acyl-ACP thioesterases. Plant Cell 7 359-371. 

Fig. 3. Generic reaction sequence for the FASs. ACP, acyl carrier protein AT, acetyltransferase MT, malonyl transferase KS, P-ketoacyl synthase KR, P-ketoacyl reductase DH, dehydrase ER, enoyl reductase TE, thioesterase FT, palmitoyl transferase. In the animal FAS the acetyl and malonyl loading reactions are catalyzed by the same acyl transferase and the chain-termination reaction is catalyzed by a thioesterase. In the fungal FAS, the malonyl loading and palmitoyl unloading reactions are catalyzed by the same acyl transferase. Stereochemical analyses in the laboratories of Comforth and Hammes established that in both animal and fungal FASs the KS-catalyzed condensation reaction proceeds with inversion of configuration at the malonyl C2 position, followed by KR-catalyzed reduction of the 3-keto moiety to the 3R alcohol by transfer of the pro-4S hydride from NADPH, and DH-catalyzed dehydration to a trans-enoyl moiety by the syn elimination of the 2S hydrogen and the 3/f hydroxyl as water. However, the stereochemistry of the final reduction reaction catalyzed by ER domain proceeds with different stereochemistry. The animal FAS transfers the pro-4R hydride of NADPH to the pro-3/f position with simultaneous addition of a solvent proton to the pro-2S position, whereas the fungal FAS takes the pro-4S hydride of NADPH into the pro-3S position and the solvent proton is incorporated at the pro-25 position.

The three main products formed during the FA synthesis in the stroma of the plastid are hydrolyzed by two possible acyl-ACP thioesterases (FAT) FAT A and FAT B. FAT A has preference for oleoyl-ACP but also hydrolyzes stearoyl- and palmitoyl-ACP. FAT B, which has preference for saturated FA-ACP and especially palmitoyl-ACP, can also hydrolyze oleoyl-ACP (Voelker Kinney, 2001). 

Infantile neuronal ceroid Palmitoyl protein thioesterase 1 0.013 live births [17,18]... 

S-Palmitoy lation Palmitoyl Protein Thioesterases (PPT) Side chain of Cys Yes Intracellular plasma membrane. Vesicle H-Ras, Gsa... 

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