Kornhuber Johannes, Tripal Philipp, Reichel Martin, Mühle Christiane, Rhein Cosima, Muehlbacher Markus, Groemer Teja W, Gulbins Erich
Department of Psychiatry and Psychotherapy, University of Erlangen, Erlangen, Germany.
Cell Physiol Biochem. 2010;26(1):9-20. doi: 10.1159/000315101. Epub 2010 May 18.
Acid sphingomyelinase (ASM) is an important lipid-metabolizing enzyme cleaving sphingomyelin to ceramide, mainly within lysosomes. Acid ceramidase (AC) further degrades ceramide to sphingosine which can then be phosphorylated to sphingosine-1-phosphate. Ceramide and its metabolite sphingosine-1-phosphate have been shown to antagonistically regulate apoptosis, cellular differentiation, proliferation and cell migration. Inhibitors of ASM or AC therefore hold promise for a number of new clinical therapies, e.g. for Alzheimer's disease and major depression on the one hand and cancer on the other. Inhibitors of ASM have been known for a long time. Cationic amphiphilic substances induce the detachment of ASM protein from inner lysosomal membranes with its consecutive inactivation, thereby working as functional inhibitors of ASM. We recently experimentally identified a large number of hitherto unknown functional inhibitors of ASM and determined specific physicochemical properties of such cationic amphiphilic substances that functionally inhibit ASM. We propose the acronym "FIASMA" (Functional Inhibitor of Acid SphingoMyelinAse) for members of this large group of compounds with a broad range of new clinical indications. FIASMAs differ markedly with respect to molecular structure and current clinical indication. Most of the available FIASMAs are licensed for medical use in humans, are minimally toxic and may therefore be applied for disease states associated with increased activity of ASM.
酸性鞘磷脂酶（ASM）是一种重要的脂质代谢酶，主要在溶酶体内将鞘磷脂裂解为神经酰胺。酸性神经酰胺酶（AC）进一步将神经酰胺降解为鞘氨醇，然后鞘氨醇可被磷酸化为1-磷酸鞘氨醇。已证明神经酰胺及其代谢产物1-磷酸鞘氨醇对细胞凋亡、分化、增殖和细胞迁移具有拮抗调节作用。因此，ASM或AC的抑制剂有望用于多种新的临床治疗，例如一方面用于治疗阿尔茨海默病和重度抑郁症，另一方面用于治疗癌症。ASM抑制剂已为人所知很长时间了。阳离子两亲性物质可诱导ASM蛋白从溶酶体内膜脱离并使其连续失活，从而作为ASM的功能性抑制剂发挥作用。我们最近通过实验鉴定出大量迄今未知的ASM功能性抑制剂，并确定了这类功能性抑制ASM的阳离子两亲性物质的特定物理化学性质。我们为这一大类具有广泛新临床适应症的化合物成员提出了首字母缩写词“FIASMA”（酸性鞘磷脂酶的功能性抑制剂）。FIASMA在分子结构和当前临床适应症方面有显著差异。大多数现有的FIASMA已获得人类医疗使用许可，毒性极小，因此可用于与ASM活性增加相关的疾病状态。
