A novel phosphodiesterase inhibitor for the treatment of chronic liver injury and metabolic diseases.

Background And Aims: Chronic liver disease leads to ~2 million deaths annually. Cyclic AMP (cAMP) signaling has long been studied in liver injury, particularly in the regulation of fatty acid (FA) β-oxidation and pro-inflammatory polarization of tissue-resident lymphocytes. Phosphodiesterase 4B inhibition has been explored as a therapeutic modality, but these drugs have had limited success and are known to cause significant adverse effects.

counters organic acid anion-mediated inhibition of peptidoglycan cross-linking through robust alanine racemase activity.

Weak organic acids are commonly found in host niches colonized by bacteria, and they can inhibit bacterial growth as the environment becomes acidic. This inhibition is often attributed to the toxicity resulting from the accumulation of high concentrations of organic anions in the cytosol, which disrupts cellular homeostasis. However, the precise cellular targets that organic anions poison and the mechanisms used to counter organic anion intoxication in bacteria have not been elucidated.

The mycothiol -transferase is divalent metal-dependent for mycothiol binding and transfer.

Mycothiol -transferase (MST) (encoded by the gene) was previously identified as the enzyme responsible for the transfer of Mycothiol (MSH) to xenobiotic acceptors in () during xenobiotic stress. To further characterize the functionality of MST and the possible roles , X-ray crystallographic, metal-dependent enzyme kinetics, thermal denaturation studies, and antibiotic MIC determination in knockout strain were performed. The binding of MSH and Zn increases the melting temperature by 12.

Structural and Functional Characterization of Homoserine Transacetylase.

() lacking functional homoserine transacetylase (HTA) is compromised in methionine biosynthesis, protein synthesis, and in the activity of multiple essential -adenosyl-l-methionine-dependent enzymes. Additionally, deficient mutants are further disarmed by the toxic accumulation of lysine due to a redirection of the metabolic flux toward the lysine biosynthetic pathway. Studies with deletion mutants and crystallographic studies of the apoenzyme have, respectively, validated HTA as an essential enzyme and revealed a ligandable binding site.