1. N-acetyl-L-glutamic acid
A J Dobson, R E Gerkin Acta Crystallogr C. 1997 Jan 15;53 ( Pt 1):73-6. doi: 10.1107/s0108270196011882.
In the structure of N-acetyl-L-glutamic acid, C7H11NO5, each molecule is directly hydrogen bonded to four others by a total of six hydrogen bonds. Two carboxylic O atoms and the N atom are donors, while all three acceptors are O atoms. There is also an intramolecular hydrogen bond with the N atom as donor and a carboxylic O atom as acceptor. The carboxyl O and H atoms are ordered. The conformation of the carbon chain with respect to the C3-C4 bond is trans as in L-glutamic acid hydrochloride, rather than gauche as in the beta form of L-glutamic acid.
2. Antidepressant effects of ketamine in depressed patients
R M Berman, A Cappiello, A Anand, D A Oren, G R Heninger, D S Charney, J H Krystal Biol Psychiatry. 2000 Feb 15;47(4):351-4. doi: 10.1016/s0006-3223(99)00230-9.
Background: A growing body of preclinical research suggests that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. This is the first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression. Methods: Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) or saline solutions under randomized, double-blind conditions. Results: Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 +/- SD 10 points vs. 0 +/- 12 points, respectively during active and sham treatment). Conclusions: These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.
3. Discovery of a potent SCAP degrader that ameliorates HFD-induced obesity, hyperlipidemia and insulin resistance via an autophagy-independent lysosomal pathway
Zu-Guo Zheng, et al. Autophagy. 2021 Jul;17(7):1592-1613. doi: 10.1080/15548627.2020.1757955. Epub 2020 May 20.
SCAP (SREBF chaperone) regulates SREBFs (sterol regulatory element binding transcription factors) processing and stability, and, thus, becomes an emerging drug target to treat dyslipidemia and fatty liver disease. However, the current known SCAP inhibitors, such as oxysterols, induce endoplasmic reticulum (ER) stress and NR1H3/LXRα (nuclear receptor subfamily 1 group H member 3)-SREBF1/SREBP-1 c-mediated hepatic steatosis, which severely limited the clinical application of this inhibitor. In this study, we identified a small molecule, lycorine, which binds to SCAP, which suppressed the SREBF pathway without inducing ER stress or activating NR1H3. Mechanistically, lycorine promotes SCAP lysosomal degradation in a macroautophagy/autophagy-independent pathway, a mechanism completely distinct from current SCAP inhibitors. Furthermore, we determined that SQSTM1 captured SCAP after its exit from the ER. The interaction of SCAP and SQSTM1 requires the WD40 domain of SCAP and the TB domain of SQSTM1. Interestingly, lycorine triggers the lysosome translocation of SCAP independent of autophagy. We termed this novel protein degradation pathway as the SQSTM1-mediated autophagy-independent lysosomal degradation (SMAILD) pathway. In vivo, lycorine ameliorates high-fat diet-induced hyperlipidemia, hepatic steatosis, and insulin resistance in mice. Our study demonstrated that the inhibition of SCAP through the SMAILD pathway could be employed as a useful therapeutic strategy for treating metabolic diseases.
