Fas pathway

Like the related fatty acid synthases (FASs), polyketide synthases (PKSs) are multifunctional enzymes that catalyze the decarboxylative (Claisen) condensation of simple carboxylic acids, activated as their coenzyme A (CoA) thioesters. While FASs typically use acetyl-CoA as the starter unit and malonyl-CoA as the extender unit, PKSs often employ acetyl- or propionyl-CoA to initiate biosynthesis, and malonyl-, methylmalonyl-, and occasionally ethylmalonyl-CoA or pro-pylmalonyl-CoA as a source of chain-extension units. After each condensation, FASs catalyze the full reduction of the P-ketothioester to a methylene by way of ketoreduction, dehydration, and enoyl reduction (Fig. 3). In contrast, PKSs shortcut the FAS pathway in one of two ways (Fig. 4). The aromatic PKSs (Fig. 4a) leave the P-keto groups substantially intact to produce aromatic products, while the modular PKSs (Fig. 4b) catalyze a variable extent of reduction to yield the so-called complex polyketides. In the latter case, reduction may not occur, or there may be formation of a P-hydroxy, double-bond, or fully saturated methylene additionally, the outcome may vary between different cycles of chain extension (Fig. 4b). This inherent variability in keto reduction, the greater variety of... 

Lee P, Sata M, Lefer DJ, Factor SM, Walsh K, Kitsis RN. Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion in vivo. Am J Physiol Heart Circ Physiol 2003 284 H456-H463. 

Li M, Ona VO, Guegan C, Chen M, Jackson-Lewis V, Andrews LJ, Olszewski AJ, Stieg PE, Lee JP, Przedborski S, Friedlander RM (2000) Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 288 335-339 Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94 491-501 Lin Y, Devin A, Cook A, Keane MM, Kelliher M, Lipkowitz S, Liu ZG (2000) The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of IkappaB kinase and c-Jun N-terminal kinase. Mol Cell Biol 20 6638-6645... 

Complete depletions of BRCAl and BRCA2 proteins, which appear to act in the Fanconi anemia repair pathway of interstrand cross-hnks and maintenance of genome stability, leads to cell lethality. Thus, instead of gene knock out, siRNA was used to transiently deplete the expression in order to better understand the function of the proteins [89]. It was shown that BRCA2 acts late in the FA response to interstrand cross hnks, whereas BRCAl must act early in the FA response and has at least one additional role in interstrand cross-hnk repair outside the FA pathway. 

Recent studies with bovine heart mitochondrial matrix preparations indicate that one of the major products of this pathway is octanoyl-ACP and these newly synthesized octanoyl moieties can be translocated directly to the lipoylation site of the glycine cleavage apo-H protein (S. Smith, 2007). Octanoylated mitochondrial proteins are the substrates for the enzyme lipoic acid synthase, which inserts two sulfur atoms at the C6 and C8 positions of the octanoyl moiety. These results are consistent with the hypothesis that one of the major roles of the mitochondrial FAS pathway in all eukaryotes is to ensure that an adequate supply of lipoyl moieties is always available to service the glycine cleavage enzyme and the alpha-ketoacid dehydrogenases that are essential to mitochondrial function. 

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