ELIZA cgi-bash version rev. 1.91
- Medical English LInking keywords finder for the PubMed Zipped Archive (ELIZA) -

return kwic search for levels out of >500 occurrences
501283 occurrences (No.27 in the rank) during 5 years in the PubMed. [cache]
291) Increased NAA levels in the brains of affected children are one of the hallmarks of CD.
--- ABSTRACT ---
PMID:34477360 DOI:10.1021/acschemneuro.1c00455
2021 ACS chemical neuroscience
* High Throughput Screening Cascade To Identify Human Aspartate N-Acetyltransferase (ANAT) Inhibitors for Canavan Disease.
- Canavan disease (CD) is a progressive, fatal neurological disorder that begins in infancy resulting from a mutation in aspartoacyclase (ASPA), an enzyme that catalyzes the deacetylation of N-acetyl aspartate (NAA) into acetate and aspartate. Increased NAA levels in the brains of affected children are one of the hallmarks of CD. Interestingly, genetic deletion of N-acetyltransferase-8-like (NAT8L), which encodes aspartate N-aceyltransferase (ANAT), an enzyme responsible for the synthesis of NAA from l-aspartate and acetyl-CoA, leads to normalization of NAA levels and improvement of symptoms in several genetically engineered mouse models of CD. Therefore, pharmacological inhibition of ANAT presents a promising therapeutic strategy for treating CD. Currently, however, there are no clinically viable ANAT inhibitors. Herein we describe the development of fluorescence-based high throughput screening (HTS) and radioactive-based orthogonal assays using recombinant human ANAT expressed in E. coli. In the fluorescence-based assay, ANAT activity was linear with respect to time of incubation up to 30 min and protein concentration up to 97.5 ng/μL with Km values for l-aspartate and acetyl-CoA of 237 μM and 11 μM, respectively. Using this optimized assay, we conducted a pilot screening of a 10 000-compound library. Hits from the fluorescence-based assay were subjected to an orthogonal radioactive-based assay using L-[U-14C] aspartate as a substrate. Two compounds were confirmed to have dose-dependent inhibition in both assays. Inhibitory kinetics studies of the most potent compound revealed an uncompetitive inhibitory mechanism with respect to l-aspartate and a noncompetitive inhibitory mechanism against acetyl-CoA. The screening cascade developed herein will enable large-scale compound library screening to identify novel ANAT inhibitors as leads for further medicinal chemistry optimization.
--- ABSTRACT END ---
[
right
kwic]
[frequency of next (right) word to levels]
(1)199 of (8)6 to (15)2 among (22)2 on
(2)57 *null* (9)4 for (16)2 as (23)2 that
(3)39 in (10)4 the (17)2 can (24)2 there
(4)36 and (11)3 at (18)2 comparable (25)2 through
(5)14 were (12)3 which (19)2 have (26)2 was
(6)11 are (13)2 (p (20)2 however, (27)2 while
(7)7 by (14)2 after (21)2 is

add keyword

--- WordNet output for levels --- Overview of noun level The noun level has 8 senses (first 6 from tagged texts) 1. (69) degree, grade, level -- (a position on a scale of intensity or amount or quality; "a moderate grade of intelligence"; "a high level of care is required"; "it is all a matter of degree") 2. (22) grade, level, tier -- (a relative position or degree of value in a graded group; "lumber of the highest grade") 3. (15) degree, level, stage, point -- (a specific identifiable position in a continuum or series or especially in a process; "a remarkable degree of frankness"; "at what stage are the social sciences?") 4. (5) level -- (height above ground; "the water reached ankle level"; "the pictures were at the same level") 5. (1) level, spirit level -- (indicator that establishes the horizontal when a bubble is centered in a tube of liquid) 6. (1) horizontal surface, level -- (a flat surface at right angles to a plumb line; "park the car on the level") 7. level, layer, stratum -- (an abstract place usually conceived as having depth; "a good actor communicates on several levels"; "a simile has at least two layers of meaning"; "the mind functions on many strata simultaneously") 8. floor, level, storey, story -- (a structure consisting of a room or set of rooms at a single position along a vertical scale; "what level is the office on?") Overview of verb level The verb level has 6 senses (first 3 from tagged texts) 1. (4) level -- (aim at; "level criticism or charges at somebody") 2. (1) level, raze, rase, dismantle, tear down, take down, pull down -- (tear down so as to make flat with the ground; "The building was levelled") 3. (1) flush, level, even out, even -- (make level or straight; "level the ground") 4. charge, level, point -- (direct into a position for use; "point a gun"; "He charged his weapon at me") 5. level -- (talk frankly with; lay it on the line; "I have to level with you") 6. level, level off -- (become level or even; "The ground levelled off") --- WordNet end ---