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7 Publications visible to you, out of a total of 7
Natural isotope correction improves analysis of protein modification dynamics

Abstract (Expand)

Abstract Stable isotope labelling in combination with high-resolution mass spectrometry approaches are increasingly used to analyze both metabolite and protein modification dynamics. To enable correct …ynamics. To enable correct estimation of the resulting dynamics, it is critical to correct the measured values for naturally occurring stable isotopes, a process commonly called isotopologue correction or deconvolution. While the importance of isotopologue correction is well recognized in metabolomics, it has received far less attention in proteomics approaches. Although several tools exist that enable isotopologue correction of mass spectrometry data, the majority is tailored for the analysis of low molecular weight metabolites. We here present PICor which has been developed for isotopologue correction of complex isotope labelling experiments in proteomics or metabolomics and demonstrate the importance of appropriate correction for accurate determination of protein modifications dynamics, using histone acetylation as an example.

Authors: Jörn Dietze, Alienke van Pijkeren, Anna-Sophia Egger, Mathias Ziegler, Marcel Kwiatkowski, Ines Heiland

Date Published: 1st Dec 2021

Publication Type: Journal

Welcome to the Family: Identification of the NAD(+) Transporter of Animal Mitochondria as Member of the Solute Carrier Family SLC25.

Abstract (Expand)

Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across … their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective transport of molecules such as nucleotides, amino acids, and sugars across biological membranes. Research over many years has identified the localization and preferred substrates of a large variety of SLCs. Of particular interest has been the SLC25 family, which includes carriers embedded in the inner membrane of mitochondria to secure the supply of these organelles with major metabolic intermediates and coenzymes. The substrate specificity of many of these carriers has been established in the past. However, the route by which animal mitochondria are supplied with NAD(+) had long remained obscure. Only just recently, the existence of a human mitochondrial NAD(+) carrier was firmly established. With the realization that SLC25A51 (or MCART1) represents the major mitochondrial NAD(+) carrier in mammals, a long-standing mystery in NAD(+) biology has been resolved. Here, we summarize the functional importance and structural features of this carrier as well as the key observations leading to its discovery.

Authors: M. Ziegler, M. Monne, A. Nikiforov, G. Agrimi, I. Heiland, F. Palmieri

Date Published: 14th Jun 2021

Publication Type: Journal

Identification of evolutionary and kinetic drivers of NAD-dependent signaling.

Abstract (Expand)

Nicotinamide adenine dinucleotide (NAD) provides an important link between metabolism and signal transduction and has emerged as central hub between bioenergetics and all major cellular events. … NAD-dependent signaling (e.g., by sirtuins and poly-adenosine diphosphate [ADP] ribose polymerases [PARPs]) consumes considerable amounts of NAD. To maintain physiological functions, NAD consumption and biosynthesis need to be carefully balanced. Using extensive phylogenetic analyses, mathematical modeling of NAD metabolism, and experimental verification, we show that the diversification of NAD-dependent signaling in vertebrates depended on 3 critical evolutionary events: 1) the transition of NAD biosynthesis to exclusive usage of nicotinamide phosphoribosyltransferase (NamPT); 2) the occurrence of nicotinamide N-methyltransferase (NNMT), which diverts nicotinamide (Nam) from recycling into NAD, preventing Nam accumulation and inhibition of NAD-dependent signaling reactions; and 3) structural adaptation of NamPT, providing an unusually high affinity toward Nam, necessary to maintain NAD levels. Our results reveal an unexpected coevolution and kinetic interplay between NNMT and NamPT that enables extensive NAD signaling. This has implications for therapeutic strategies of NAD supplementation and the use of NNMT or NamPT inhibitors in disease treatment.

Authors: M. Bockwoldt, D. Houry, M. Niere, T. I. Gossmann, I. Reinartz, A. Schug, M. Ziegler, I. Heiland

Date Published: 6th Aug 2019

Publication Type: Journal

Identification of evolutionary and kinetic drivers of NAD-dependent signaling

Abstract

Not specified

Authors: Mathias Bockwoldt, Dorothée Houry, Marc Niere, Toni I. Gossmann, Ines Reinartz, Alexander Schug, Mathias Ziegler, Ines Heiland

Date Published: 6th Aug 2019

Publication Type: Journal

Identification of evolutionary and kinetic drivers of NAD-dependent signaling

Abstract (Expand)

Nicotinamide adenine dinucleotide (NAD) provides an important link between metabolism and signal transduction and has emerged as central hub between bioenergetics and all major cellular events. …llular events. NAD-dependent signaling (e.g., by sirtuins and poly–adenosine diphosphate [ADP] ribose polymerases [PARPs]) consumes considerable amounts of NAD. To maintain physiological functions, NAD consumption and biosynthesis need to be carefully balanced. Using extensive phylogenetic analyses, mathematical modeling of NAD metabolism, and experimental verification, we show that the diversification of NAD-dependent signaling in vertebrates depended on 3 critical evolutionary events: 1) the transition of NAD biosynthesis to exclusive usage of nicotinamide phosphoribosyltransferase (NamPT); 2) the occurrence of nicotinamide N-methyltransferase (NNMT), which diverts nicotinamide (Nam) from recycling into NAD, preventing Nam accumulation and inhibition of NAD-dependent signaling reactions; and 3) structural adaptation of NamPT, providing an unusually high affinity toward Nam, necessary to maintain NAD levels. Our results reveal an unexpected coevolution and kinetic interplay between NNMT and NamPT that enables extensive NAD signaling. This has implications for therapeutic strategies of NAD supplementation and the use of NNMT or NamPT inhibitors in disease treatment.

Authors: Mathias Bockwoldt, Dorothée Houry, Marc Niere, Toni I. Gossmann, Ines Reinartz, Alexander Schug, Mathias Ziegler, Ines Heiland

Date Published: 6th Aug 2019

Publication Type: Journal

Subcellular Distribution of NAD+ between Cytosol and Mitochondria Determines the Metabolic Profile of Human Cells.

Abstract (Expand)

The mitochondrial NAD pool is particularly important for the maintenance of vital cellular functions. Although at least in some fungi and plants, mitochondrial NAD is imported from the cytosol by carrier … proteins, in mammals, the mechanism of how this organellar pool is generated has remained obscure. A transporter mediating NAD import into mammalian mitochondria has not been identified. In contrast, human recombinant NMNAT3 localizes to the mitochondrial matrix and is able to catalyze NAD(+) biosynthesis in vitro. However, whether the endogenous NMNAT3 protein is functionally effective at generating NAD(+) in mitochondria of intact human cells still remains to be demonstrated. To modulate mitochondrial NAD(+) content, we have expressed plant and yeast mitochondrial NAD(+) carriers in human cells and observed a profound increase in mitochondrial NAD(+). None of the closest human homologs of these carriers had any detectable effect on mitochondrial NAD(+) content. Surprisingly, constitutive redistribution of NAD(+) from the cytosol to the mitochondria by stable expression of the Arabidopsis thaliana mitochondrial NAD(+) transporter NDT2 in HEK293 cells resulted in dramatic growth retardation and a metabolic shift from oxidative phosphorylation to glycolysis, despite the elevated mitochondrial NAD(+) levels. These results suggest that a mitochondrial NAD(+) transporter, similar to the known one from A. thaliana, is likely absent and could even be harmful in human cells. We provide further support for the alternative possibility, namely intramitochondrial NAD(+) synthesis, by demonstrating the presence of endogenous NMNAT3 in the mitochondria of human cells.

Authors: M. R. VanLinden, C. Dolle, I. K. Pettersen, V. A. Kulikova, M. Niere, G. Agrimi, S. E. Dyrstad, F. Palmieri, A. A. Nikiforov, K. J. Tronstad, M. Ziegler

Date Published: 13th Nov 2015

Publication Type: Not specified

Model of tryptophan metabolism, readily scalable using tissue-specific gene expression data.

Abstract (Expand)

Tryptophan is utilized in various metabolic routes including protein synthesis, serotonin, and melatonin synthesis and the kynurenine pathway. Perturbations in these pathways have been associated with … neurodegenerative diseases and cancer. Here we present a comprehensive kinetic model of the complex network of human tryptophan metabolism based upon existing kinetic data for all enzymatic conversions and transporters. By integrating tissue-specific expression data, modeling tryptophan metabolism in liver and brain returned intermediate metabolite concentrations in the physiological range. Sensitivity and metabolic control analyses identified expected key enzymes to govern fluxes in the branches of the network. Combining tissue-specific models revealed a considerable impact of the kynurenine pathway in liver on the concentrations of neuroactive derivatives in the brain. Moreover, using expression data from a cancer study predicted metabolite changes that resembled the experimental observations. We conclude that the combination of the kinetic model with expression data represents a powerful diagnostic tool to predict alterations in tryptophan metabolism. The model is readily scalable to include more tissues, thereby enabling assessment of organismal tryptophan metabolism in health and disease.

Authors: A. K. Stavrum, I. Heiland, S. Schuster, P. Puntervoll, M. Ziegler

Date Published: 29th Nov 2013

Publication Type: Journal

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