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BackgroundHydroxycinnamoyl-spermine conjugates (HCSpm) are a class of hydroxycinnamic acid amides (HCAAs), which not only are instrumental in plant development and stress response, but also benefit human health. However, HCSpm are not commonly produced in plants, and the mechanism of their biosynthesis remains unclear. In previous investigations of phenolics in Solanum fruits related to eggplant (Solanum melongena L.), we discovered that Solanum richardii, an African wild relative of eggplant, was rich in HCSpms in fruits.ResultsThe putative spermine hydroxycinnamoyl transferase (HT) SpmHT was isolated from S. richardii and eggplant. SrSpmHT expression was high in flowers and fruit, and was associated with HCSpm accumulation in S. richardii; however, SpmHT was hardly detected in eggplant cultivars and other wild relatives. Recombinant SpmHT exclusively selected spermine as the acyl acceptor substrate, while showing donor substrate preference in the following order: caffeoyl-CoA, feruloyl-CoA, and p-coumaroyl-CoA. Molecular docking revealed that substrate binding pockets of SpmHT could properly accommodate spermine but not the shorter, more common spermidine.ConclusionSrSpmHT is a novel spermine hydroxycinnamoyl transferase that uses Spm exclusively as the acyl acceptor substrate to produce HCSpms. Our findings shed light on the HCSpm biosynthetic pathway that may allow an increase of health beneficial metabolites in Solanum crops via methods such as introgression or engineering HCAA metabolism.

The specific Sirt1 activator SRT1720 increases mitochondrial function in skeletal muscle, presumably by activating Sirt1. However, Sirt1 gain of function does not increase mitochondrial function, which raises a question about the central role of Sirt1 in SRT1720 action. Moreover, it is believed that the metabolic effects of SRT1720 occur independently of AMP-activated protein kinase (AMPK), an important metabolic regulator that increases mitochondrial function. Here, we show that SRT1720 activates AMPK in a Sirt1-independent manner and SRT1720 activates AMPK by inhibiting a cAMP degrading phosphodiesterase (PDE) in a competitive manner. Inhibiting the cAMP effector protein Epac prevents SRT1720 from activating AMPK or Sirt1 in myotubes. Moreover, SRT1720 does not increase mitochondrial function or improve glucose tolerance in AMPKα2 knockout mice. Interestingly, weight loss induced by SRT1720 is not sufficient to improve glucose tolerance. Therefore, contrary to current belief, the metabolic effects produced by SRT1720 require AMPK, which can be activated independently of Sirt1.

Neurodegenerative diseases (NDs) cause progressive loss of neuron structure and ultimately lead to neuronal cell death. Since the available drugs show only limited symptomatic relief, NDs are currently considered as incurable. This review will illustrate the principal roles of the signaling systems of cyclic adenosine and guanosine 3′,5′‐monophosphates (cAMP and cGMP) in the neuronal functions, and summarize expression/activity changes of the associated enzymes in the ND patients, including cyclases, protein kinases, and phosphodiesterases (PDEs). As the sole enzymes hydrolyzing cAMP and cGMP, PDEs are logical targets for modification of neurodegeneration. We will focus on PDE inhibitors and their potentials as disease‐modifying therapeutics for the treatment of Alzheimer's disease, Parkinson's disease, and Huntington's disease. For the overlapped but distinct contributions of cAMP and cGMP to NDs, we hypothesize that dual PDE inhibitors, which simultaneously regulate both cAMP and cGMP signaling pathways, may have complementary and synergistic effects on modifying neurodegeneration and thus represent a new direction on the discovery of ND drugs. [ABSTRACT FROM AUTHOR]

Hyperuricemia and gout are metabolic diseases characterized with high serum urate and impact human health significantly. Although some drugs have been developed to treat gout, hyperuricemia represents a substantial health problem. Reducing purine absorption through intestinal microbiota, which can be managed through intake of probiotics, emerges as a promising way to reverse elevated serum urate. Probiotics have shown several benefits such as immune modulation and improvement of intestinal functions. Therefore, this review briefly summarizes purine metabolism and molecular mechanisms for hyperuricemia and gout with the focus on recent development on the use of probiotics to alleviate hyperuricemia and gout. [ABSTRACT FROM AUTHOR]

A comparison of the dipeptide and tetrapeptide complexes with cyclophilin A reveals differences in interactions at the active site. The binding of the dipeptides is similar to succinyl-Ala-Ala-Pro-Phe-p-nitroanilide with respect to N-terminal hydrogen bonding and hydrophobic interactions. The hydrogen bonding between the carboxyl terminus of the peptides and Arg55, the side chain conformation of Arg55, and the binding of water at the active site are, however, different. The differences suggest that the dipeptides are probably inhibitors of peptidyl-prolyl cis-trans isomerases.

Cyclophilin A catalyzes the cis to trans isomerization of a peptidyl-prolyl amide bond. Crystal structure studies of human recombinant cyclophilin A complexed to a succinyl-Ala-Ala-Pro-Phe-p-nitroanilide substrate indicate that only the cis form attachs to cyclophilin A. The trans form is unable to fit into the active site. The structure reveals that Arg55 hydrogen-bonds to the nitrogen and deconjugates the resonance of prolyl amide bond and helps in the cis-trans transition.

Results show that simultaneous interaction of two divalent metal ions with the phosphate group of AMP suggests a binuclear catalysis by phosphodiesterase as deduced from the crystal structure of the human cyclic nucleotide phosphodiesterase catalytic domain in complex with AMP at 2.4 Angstrom resolution. Further, structural data reveal that bridging two metal ions by a hydroxide ion or a water may form a nucleophile that hydrolyzes the cAMP phosphodiester bond.