Activator-Dependent Hydrolysis of Myelin Cerebroside Sulfate by Arylsulfatase A

Louis, Andrew I.; Fluharty, Arvan L.

doi:10.1159/000112139

Cited by 10 publications

(12 citation statements)

References 16 publications

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“…Additionally, the lipid chains might only partly bind to the surface of ASA and are otherwise extending outwards. This postulate is based on the fact that in vivo, SGC/SGG has to be extracted from membranes by the transporter protein saposin B and then transferred to the active site of ASA [42]. The crystal structure of saposin B [3] indicates that it exists as a dimer with an unusually large hydrophobic cavity (900 Å 3 ) that would interact with the hydrocarbon chains of SGC/SGG.…”

Section: Discussionmentioning

confidence: 99%

Interaction of arylsulfatase-A (ASA) with its natural sulfoglycolipid substrates: a computational and site-directed mutagenesis study

et al. 2009

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Arylsulfatase A (ASA) hydrolyzes sulfate esters with a pH optimum of 5. Interactions between p-nitrocatechol sulfate (NCS, artificial substrate) and active site residues of ASA are revealed from their co-crystal structure. Since equivalent ASA interactions with its natural substrates, sulfogalactosylceramide (SGC) and sulfogalactosylglycerolipid (SGG), are not known, we computationally docked SGC/SGG to the ASA crystal structure. Our dockings suggested that Cys69 was the active site residue, and Lys302 & Lys123 as residues anchoring the sulfate group of SGC/SGG to the active site, as observed for NCS. We further confirmed these results using 2 recombinant ASA mutants: C69A and CKK (Cys69, Lys302 and Lys123-all mutated to Ala). Both ASA mutants failed to desulfate SGC/SGG, and CKK showed minimal binding to [(14)C]SGC, although C69A still had affinity for this sulfoglycolipid. However, our dockings suggested additional intermolecular hydrogen bonding and hydrophobic interactions between ASA and SGC/SGG, thus contributing to the specificity of SGC/SGG as natural substrates.

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Section: Discussionmentioning

confidence: 99%

Interaction of arylsulfatase-A (ASA) with its natural sulfoglycolipid substrates: a computational and site-directed mutagenesis study

et al. 2009

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“…We are now aware that ARS-A does not act on aggregated forms of sulfolipid, such as, that encountered in the usual aqueous "solution" of purified material, or in the physiologically relevant membrane-bound form (Louis and Fluharty, 1990). Hydrolysis requires the cooperation of an additional protein element, the cerebroside sulfate activator (also known as SAP-1 or Saposin B).…”

Section: The Relationship Of the Metachroniatic Leukodystrophies To Nmentioning

confidence: 99%

The relationship of the metachromatic leukodystrophies to neuropsychiatric disorders

Fluharty

1990

Molecular and Chemical Neuropathology

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The possible relationship between the metachromatic leukodystrophies and neuropsychiatric disorders is reviewed. Four kinds of evidence are considered: psychiatric symptoms as preemergent markers of the neurodegenerative process; increased behavioral problems in leukodystrophy families; screening for low enzyme levels among psychiatric populations; and studies in model systems. Whereas the basic postulate of an increased risk for psychiatric problems among individuals with lower levels of the enzymes deficient in the leukodystrophies remains attractive, there is no strong evidence in its support. Low enzyme levels can be found in psychiatric populations, but they may not be any more frequent than in the general population.

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“…[23] Louis and Fluharty demonstrated that activator-dependent hydrolysis of myelin cerebroside sulfate by ASA could be affected in terms of slower hydrolysis rates by competition for activator by "other lipoidal constituents", as yet still unknown. [24] Based on the data herein, it is likely that SapB binding of A2E would result in competition between A2E and ASA for activator, even temporarily, which would be a significant problem for a circadian process. [25] In summary, we demonstrate that A2E binding by the lysosomal protein SapB prevents A2E oxidation by HRP or blue light.…”

Section: Introductionmentioning

confidence: 87%

Saposin B Binds the Lipofuscin Bisretinoid A2E and Prevents its Enzymatic and Photooxidation

et al. 2017

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Vitamin A based bisretinoid accumulation is a major focus in the study of macular degeneration. Whether specific endogenous lysosomal proteins can bind A2E, a pronounced bisretinoid in lipofuscin granules in retinal pigment epithelial cells, and interfere with enzymatic or photoinduced oxidation of such, has not been explored. Herein, using fluorescence and electronic absorption spectroscopy and mass spectrometry, we demonstrate that Saposin B, a critical protein in the degradation of sulfatides and "flushing" of lipids, can bind A2E, preventing its H 2 O 2 -dependent enzymatic oxidation by horseradish peroxidase and photooxidation by blue light (λ=450-460 nm). Putting a lid on itDegrading bisretenoids, understanding their cellular photochemistry and tracking their effects on cellular processes are critical in the study of age-related macular degeneration (AMD) development and treatment. Herein, we demonstrate that the vital cellular co-factor Saposin B binds A2E, a common bisretenoid found in granules in AMD patients, and prevents enzymatic and photooxidation/ degradation.Correspondence to: Fadi Bou-Abdallah; Robert P. Doyle. Conflict of interestThe authors declare no conflict of interest.Supporting Information (also containing the Experimental Section) and the ORCID identification number(s) for the author(s) of this article can be found under: http://dx

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Activator-Dependent Hydrolysis of Myelin Cerebroside Sulfate by Arylsulfatase A

Cited by 10 publications

References 16 publications

Interaction of arylsulfatase-A (ASA) with its natural sulfoglycolipid substrates: a computational and site-directed mutagenesis study

Interaction of arylsulfatase-A (ASA) with its natural sulfoglycolipid substrates: a computational and site-directed mutagenesis study

The relationship of the metachromatic leukodystrophies to neuropsychiatric disorders

Saposin B Binds the Lipofuscin Bisretinoid A2E and Prevents its Enzymatic and Photooxidation

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