Novel role for the LKB1 pathway in controlling monocarboxylate fuel transporters

A question preoccupying many researchers is how signal transduction pathways control metabolic processes and energy production. A study by Jang et al. (Jang, C., G. Lee, and J. Chung. 2008. J. Cell Biol. 183:11–17) provides evidence that in Drosophila melanogaster a signaling network controlled by the LKB1 tumor suppressor regulates trafficking of an Sln/dMCT1 monocarboxylate transporter to the plasma membrane. This enables cells to import additional energy sources such as lactate and butyrate, enhancing the repertoire of fuels they can use to power vital activities

LRRK2 kinase in Parkinson's disease

Defects in vesicular trafficking and immune responses are found in Parkinson's disease</jats:p

Leucine-Rich Repeat Kinases

Activating mutations in leucine-rich repeat kinase 2 (LRRK2) represent the most common cause of monogenic Parkinson's disease. LRRK2 is a large multidomain protein kinase that phosphorylates a specific subset of the ∼65 human Rab GTPases, which are master regulators of the secretory and endocytic pathways. After phosphorylation by LRRK2, Rabs lose the capacity to bind cognate effector proteins and guanine nucleotide exchange factors. Moreover, the phosphorylated Rabs cannot interact with their cognate prenyl-binding retrieval proteins (also known as guanine nucleotide dissociation inhibitors) and, thus, they become trapped on membrane surfaces. Instead, they gain the capacity to bind phospho-Rab-specific effector proteins, such as RILPL1, with resulting pathological consequences. Rab proteins also act upstream of LRRK2 by controlling its activation and recruitment onto membranes. LRRK2 signaling is counteracted by the phosphoprotein phosphatase PPM1H, which selectively dephosphorylates phospho-Rab proteins. We present here our current understanding of the structure, biochemical properties, and cell biology of LRRK2 and its related paralog LRRK1 and discuss how this information guides the generation of LRRK2 inhibitors for the potential benefit of patients.</p

Terpyridine Diphosphine Ruthenium Complexes as Efficient Photocatalysts for the Transfer Hydrogenation of Carbonyl Compounds

Over the past decade, visible-light photoredox catalysis or photocatalysis has grown to become a commonly employed powerful tool in organic synthesis leading to new unique and valuable molecular transformations, inaccessible from thermally activated processes.[1] Photocatalysis can be conducted in homogeneous conditions as well as employing heterogeneous transition metal or solid semiconductors.[2] The commonly employed homogeneous visible-light photocatalysts are homoleptic Ru and Ir polypyridyl complexes, like [Ru(bpy)3]2+ and [Ir(ppy)3] (bpy = 2,2’-bipyridine; ppy = 2-phenylpyridine). These compounds, when excited by visible light undergo a metal-to-ligand-charge transfer (MLCT) transitions from HOMO and LUMO orbitals of the ligand.[3] The 2,2’:6’,2”- terpyridine (tpy) is an NNN-type Pincer ligand, which can give tight chelation of various metal cations in a nearly planar geometry. The presence of the electron-deficient pyridine cycles make it a strong σ-donor and also as a very good π-receptor, moreover the presence of low energetic LUMO levels allows it to participate in the redox reactions as a non-innocent ligand.[4] Among the catalytical reactions, the transfer hydrogenation (TH) of carbonyl compounds promoted by Ru complexes is a core process for the synthesis of alcohols in an environmentally friendly and widely accepted method in industry.[5] We report herein a practical and innovative procedure for the synthesis of a new class of ruthenium cationic [RuX(PP)(tpy)]Y (PP = diphosphine; X = Cl, OAc; Y = Cl, OAc, PF6) complexes containing tpy and a suitable diphosphine (Figure 1). These cationic complexes are active visible-light photocatalysts for the TH of carbonyl compounds at 30 °C in 2- propanol

Pincer and Carbonyl Ruthenium Complexes for Transfer Hydrogenation Reactions

The transfer hydrogenation (TH) catalyzed by ruthenium complexes is a cost-effective and environmentally benign way for the reduction of carbonyl compounds. On account of the reversibility of the TH process, ruthenium catalysts have attracted a great deal of interest for a number of C-H activation organic transformations. To improve the catalytic activity and to retard decomposition, the design of suitable chelating and non-innocent ligands appears crucial. We report here the preparation of pincer, carbonyl and acetate ruthenium complexes, displaying high productivity for the TH of carbonyl compounds, including flavanones and biomass-derived molecules (5-HMF, ethyl levulinate). The alkylation of amines with alcohols and the preliminary results on the photochemical TH of carbonyl compounds are also presented