Ubiquitination Links DNA Damage and Repair Signaling to Cancer Metabolism.

Changes in the DNA damage response (DDR) and cellular metabolism are two important factors that allow cancer cells to proliferate. DDR is a set of events in which DNA damage is recognized, DNA repair factors are recruited to the site of damage, the lesion is repaired, and cellular responses associated with the damage are processed. In cancer, DDR is commonly dysregulated, and the enzymes associated with DDR are prone to changes in ubiquitination. Additionally, cellular metabolism, especially glycolysis, is upregulated in cancer cells, and enzymes in this metabolic pathway are modulated by ubiquitination. The ubiquitin-proteasome system (UPS), particularly E3 ligases, act as a bridge between cellular metabolism and DDR since they regulate the enzymes associated with the two processes. Hence, the E3 ligases with high substrate specificity are considered potential therapeutic targets for treating cancer. A number of small molecule inhibitors designed to target different components of the UPS have been developed, and several have been tested in clinical trials for human use. In this review, we discuss the role of ubiquitination on overall cellular metabolism and DDR and confirm the link between them through the E3 ligases NEDD4, APC/CCDH1, FBXW7, and Pellino1. In addition, we present an overview of the clinically important small molecule inhibitors and implications for their practical use.

Identification of Antihypertensive Peptides Derived from Low Molecular Weight Casein Hydrolysates Generated during Fermentation by Bifidobacterium longum KACC 91563.

Angiotensin-converting enzyme (ACE) inhibitory activity was evaluated for the low-molecular-weight fraction (<3 kDa) obtained from milk fermentation by Bifidobacterium longum KACC91563. The ACE inhibitory activity in this fraction was 62.3%. The peptides generated from the <3 kDa fraction were identified by liquid chromatography-electrospray ionization quantitative time-of-flight mass spectrometry analysis. Of the 28 peptides identified, 11 and 16 were identified as ß-casein (CN) and αs1-CN, respectively. One peptide was identified as κ-CN. Three peptides, YQEPVLGPVRGPFPIIV, QEPVLGPVRGPFPIIV, and GPVRGPFPIIV, from ß-CN corresponded to known antihypertensive peptides. We also found 15 peptides that were identified as potential antihypertensive peptides because they included a known antihypertensive peptide fragment. These peptides were as follows: RELEELNVPGEIVE (f1-14), YQEPVLGPVRGPFP (f193-206), EPVLGPVRGPFPIIV (f195-206), PVLGPVRGPFPIIV (f196-206), VLGPVRGPFPIIV (f197-206), and LGPVRGPFPIIV (f198-206) for ß-CN; and APSFSDIPNPIGSENSEKTTMPLW (f176-199), SFSDIPNPIGSENSEKT- TMPLW (f178-199), FSDIPNPIGSENSEKTTMPLW (f179-199), SDIPNPIGSENSEKTTMPLW (f180-199), DIPNPIGSENSEKTTMPLW (f181-199), IPNPIGSENSEKTTMPLW (f182-199), PIGSENSEKTTMPLW (f185-199), IGSENSEKTTMPLW (f186-199), and SENSEKTTMPLW (f188-199) for αs1-CN. From these results, B. longum could be used as a starter culture in combination with other lactic acid bacteria in the dairy industry, and/or these peptides could be used in functional food manufacturing as additives for the development of a product with beneficial effects for human health.