Theo Wallimann

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• PhD
• Professor emeritus at ETH Zurich

Biochemical Journal 281 (Pt1) :21.40 (1992) Impact Factor 4.40

The pleiotropic effects of creatine (Cr) are based mostly on the functions of the enzyme creatine kinase (CK) and its high-energy product phosphocreatine (PCr). Multidisciplinary studies have established molecular, cellular, organ and somatic functions of the CK/PCr system, in particular for cells and tissues with high and intermittent energy fluct...

Inactivating mutations in the protein kinase LKB1 lead to a dominantly inherited cancer in humans termed Peutz-Jeghers syndrome. The role of LKB1 is unclear, and only one target for LKB1 has been identified in vivo [3]. AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that plays a pivotal role in energy ho...

Creatine kinase (CK, EC 2.7.3.2), an enzyme important for energy metabolism in cells of high and fluctuating energy requirements, catalyses the reversible transfer of a phosphoryl goup from phosphocreatine to ADP. We have solved the structure of the octameric mitochondrial isoform, Mib-CK, which is located in the intermembrane compartment and along...

Heterotrimeric AMP-activated protein kinase (AMPK) is crucial for energy homeostasis of eukaryotic cells and organisms. Here we report on (i) bacterial expression of untagged mammalian AMPK isoform combinations, all containing gamma(1), (ii) an automated four-dimensional purification protocol, and (iii) biophysical characterization of AMPK heterotr...

Creatine is a natural nitrogenous organic acid that is integral to energy metabolism and crucial for proper cell functioning. The kidneys are involved in the first step of creatine production. With kidney transplantation being the gold-standard treatment for end-stage kidney disease, kidney transplant recipients (KTR) may be at risk of impaired cre...

Nutritional habits can have a significant impact on cardiovascular health and disease. This may also apply to cardiotoxicity caused as a frequent side effect of chemotherapeutic drugs, such as doxorubicin (DXR). The aim of this work was to analyze if diet, in particular creatine (Cr) supplementation, can modulate cardiac biochemical (energy status,...

Objective: : Hypertension is a major risk factor for cardiovascular disease, kidney disease, and premature death. Increased levels of creatine kinase are associated with development of hypertension. However, it is unknown if creatine, a substrate of CK, is associated with the development of hypertension. We therefore, aimed to investigate the asso...

There is great need for the identification of new, potentially modifiable risk factors for the poor health-related quality of life (HRQoL) and of the excess risk of mortality in dialysis-dependent chronic kidney disease patients. Creatine is an essential contributor to cellular energy homeostasis, yet, on a daily basis, 1.6–1.7% of the total creati...

Based on theoretical considerations, experimental data with cells in vitro, animal studies in vivo, as well as a single case pilot study with one colitis patient, a consolidated hypothesis can be put forward, stating that "oral supplementation with creatine monohydrate (Cr), a pleiotropic cellular energy precursor, is likely to be effective in indu...

Muscle wasting, low protein intake, hypoalbuminemia, low body mass, and chronic fatigue are prevalent in hemodialysis patients. Impaired creatine status may be an often overlooked, potential contributor to these symptoms. However, little is known about creatine homeostasis in hemodialysis patients. We aimed to elucidate creatine homeostasis in hemo...

Metabolite channeling is a general mechanism to increase efficiency of sequential reactions in a metabolic pathway. It describes the transfer of intermediates between sequential enzymes without equilibration of these metabolites with the surrounding bulk solution, forming so-called metabolons or microcompartments. It is structurally based on coloca...

Background: Type 2 diabetes is associated with both impaired insulin action at target tissues and impaired insulin secretion in pancreatic beta-cells. Mitochondrial dysfunction may play a role in both insulin resistance and impaired insulin secretion. Plasma creatine has been proposed as a potential marker for mitochondrial dysfunction. We aimed t...

During recent years, creatine kinase (CK) and its substrates phosphocreatine and creatine emerged as important players in uncoupling protein 1-independent, ATP-dependent non-shivering thermogenesis in beige/brown adipocytes. The exact thermogenic mechanism, that is facilitated by the CK system, however, still remains elusive. A futile creatine-cycl...

Kreatin wird unter anderem in der Niere gebildet und wirkt ogan- und zellschützend. Die Körpersubstanz, Kreatin, kann beispielsweise bei einem Sauerstoffmangel unter der Geburt für das Kind wichtig werden. In Studien mit Stachelmäusen zeigte sich, dass eine gute Kreatin-Versorgung in der Schwangerschaft auch Zellen und Organe des Kindes schützt. We...

The CK/PCr-system, with creatine (Cr) as an energy precursor, plays a crucial role in cellular physiology. In the kidney, as in other organs and cells with high and fluctuating energy requirements, energy-charged phospho-creatine (PCr) acts as an immediate high-energy source and energy buffer, and as an intracellular energy transport vehicle. A max...

Transplantation of neural progenitor cells (NPCs) is a promising experimental therapy for Huntington's disease (HD). The variables responsible for the success of this approach, including selection of the optimal developmental stage of the grafted cells, are however largely unknown. Supporting cellular energy metabolism by creatine (Cr) supplementat...

Preclinical and clinical studies suggest that striatal transplantation of neural stem cells (NSCs) and neural progenitor cells (NPCs) may be an appealing and valuable system for treating Huntington's disease. Nevertheless, for a neural replacement to become an effective translational treatment for Huntington's disease, a certain number of difficult...

Schweiz. Zeitschrift für Ernährungsmedizin SZE 5/2014 pp 30/31

To meet high cellular demands, the energy metabolism of cardiac muscles is organized by precise and coordinated functioning of Intra-Cellular Energetic Units (ICEUs). ICEUs represent structural and functional modules integrating multiple fluxes at sites of ATP generation in mitochondria and ATP utilization by myofibrillar, sarcoplasmic reticulum an...

Subcellular microcompartments, consisting of multienzyme complexes embedded within the cellular, highly viscous matrix, associated with the cytoskeleton, or situated along membranes, are operating according to exclusion principles and favor preferred pathways of intermediates. This process, called metabolite or substrate channeling, is defined as t...

Quintessenz • Kreatin-Supplementation ist heute weitverbreitet. Millionen von professionellen Athleten sowie Freizeitsportlern und Senioren nehmen täglich Kreatin* zur Vergrösserung der Muskelmasse und Verbesserung der Muskel kraft und Leistung. • Kreatin-Präparate werden als Nahrungsergänzungsmittel kaum pharmakologisch überwacht. Daher sind Reinh...

https://www.researchgate.net/publication/233933369_Saks et al.

A broad spectrum of beneficial effects has been ascribed to creatine (Cr), phosphocreatine (PCr) and their cyclic analogues cyclo-(cCr) and phospho-cyclocreatine (PcCr). Cr is widely used as nutritional supplement in sports and increasingly also as adjuvant treatment for pathologies such as myopathies and a plethora of neurodegenerative diseases. A...

A broad spectrum of beneficial effects has been ascribed to creatine (Cr), phosphocreatine (PCr) and their cyclic analogues cyclo-(cCr) and phospho-cyclocreatine (PcCr). Cr is widely used as nutritional supplement in sports and increasingly also as adjuvant treatment for pathologies such as myopathies and a plethora of neurodegenerative diseases. A...

The creatine/creatine kinase (CK) system plays a key role in cellular energy buffering and transport. In vertebrates, CK has four isoforms expressed in a tissue-specific manner. In the process of creatine biosynthesis several other important metabolites are formed. The anticancer effect of creatine had been reported in the past, and recent literatu...

In this review we analyze the recent important and remarkable advancements in studies of compartmentation of adenine nucleotides in muscle cells due to their binding to macromolecular complexes and cellular structures, which results in non-equilibrium steady state of the creatine kinase reaction. We discuss the problems of measuring the energy flux...

The creatine/creatine kinase (CK) system plays a key role in cellular energy buffering and transport. In vertebrates, CK has four isoforms expressed in a tissue-specific manner. In the process of creatine biosynthesis several other important metabolites are formed. The anticancer effect of creatine had been reported in the past, and recent literatu...

Where Have the Fluxes Gone? • Mayis Aliev‡, • Uwe Schlattner§, • Petras Dzeja¶, • Theo Wallimann‖ and • Valdur Saks§,¹ • ‡Cardiology Research Center, Moscow, Russia, • §J. Fourier University, Grenoble, France, • ¶Mayo Clinic College of Medicine, Rochester, Minnesota, and • ‖Institute of Cell Biology, Zurich, Switzerland • 1E-mail: Valdur.Saks{at...

The metabolic sensor AMP-activated protein kinase (AMPK) regulates several transport proteins, potentially coupling transport activity to cellular stress and energy levels. The creatine transporter (CRT; SLC6A8) mediates creatine uptake into several cell types, including kidney epithelial cells, where it has been proposed that CRT is important for...

Site directed mutagenesis has shown that Ser 621 in the CBD2 sub-domain of the Ca 2þ-regulatory domain of scallop muscle Na þ-Ca 2þ exchanger (NCX-SCA) is a substrate for cAMP-PK (PK-A) in the native membrane-bound enzyme [1, 2], and under the same conditions Na þ-driven 45 Ca 2þ uptake is stimulated [3]. Examination of the amino acid sequence of N...

The mobilization of metabolic energy from adipocytes depends on a tightly regulated balance between hydrolysis and resynthesis of triacylglycerides (TAGs). Hydrolysis is stimulated by beta-adrenergic signalling to PKA that mediates phosphorylation of lipolytic enzymes, including hormone-sensitive lipase (HSL). TAG resynthesis is associated with hig...

AMP-activated protein kinase (AMPK) is a heterotrimeric complex playing a crucial role in maintaining cellular energy homeostasis. Recently, homodimerization of mammalian AMPK and yeast ortholog SNF1 was shown by us and others. In SNF1, it involved specific hydrophobic residues in the kinase domain αG-helix. Mutation of the corresponding AMPK α-sub...

Creatine synthesis takes place predominately in the kidney and liver via a two-step process involving AGAT (L-arginine:glycine amidinotransferase) and GAMT (guanidinoacetate methyltransferase). Creatine is taken into cells via the creatine transporter (CrT), where it plays an essential role in energy homeostasis, particularly for tissues with high...

The standard Akta Explorer high-performance liquid chromatography (HPLC) system has limitations for the automation of multidimensional protein purification. Here, we describe simple modifications that allow for automated multidimensional purification protocols to extend the possibilities of the Akta three-dimensional purification kit in terms of co...

The MB fraction of creatine kinase (CK-MB) has long been used as a cardiac marker. It is known that the CK-MB immunoinhibition method lacks selectivity and accuracy, because the appearance of macro CK type 2, corresponding to mitochondrial creatine kinase (MtCK) in some patient serum may render CK-MB activity measured by conventional method abnorma...

Phosphoamino acid modifications on substrate proteins are critical components of protein kinase signaling pathways. Thus, diverse methodologies have been developed and applied to identify the sites of phosphorylated amino acids within proteins. Despite significant progress in the field, even the determination of phosphorylated residues in a given h...

In: Integrated and Organized Cellular Energy Systems. Wiley Encyclopedia of Chemical Biology March 15, pages 366-392 (2009) Bioenergetics as a part of biophysical chemistry and biophysics is a quantitative science that is based on several fundamental theories.The definition of energy itself is given by the first law of thermodynamics, and applicati...

The creatine/creatine kinase system decreases drastically in sarcoma. In the present study, an investigation of catalytic activities, western blot and mRNA expression unambiguously demonstrates the prominent expression of the creatine-synthesizing enzymes l-arginine:glycine amidinotransferase and N-guanidinoacetate methyltransferase in sarcoma, Ehr...

The creatine/creatine kinase system decreases drastically in sarcoma. In the present study, an investigation of catalytic activities, western blot and mRNA expression unambiguously demonstrates the prominent expression of the creatine-synthesizing enzymes l-arginine:glycine amidinotransferase and N-guanidinoacetate methyltransferase in sarcoma, Ehr...

We have developed an automated fermentation system for cost-efficient upscaling of protein expression in bacteria. The system, built for use by nonbiotechnologists, can be assembled mostly from standard laboratory equipment and allows a largely unattended growth of bacteria to OD 25 (at 600 nm) in a 12 L vessel. The typical yield of 250-350 g of we...

Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. Accordingly, the creatine kinase/phosph...

In vertebrates, phosphocreatine and ATP are continuously interconverted by the reversible reaction of creatine kinase in accordance with cellular energy needs. Sarcoma tissue and its normal counterpart, creatine-rich skeletal muscle, are good source materials to study the status of creatine and creatine kinase with the progression of malignancy. We...

In vertebrates, phosphocreatine and ATP are continuously interconverted by the reversible reaction of creatine kinase in accordance with cellular energy needs. Sarcoma tissue and its normal counterpart, creatine-rich skeletal muscle, are good source materials to study the status of creatine and creatine kinase with the progression of malignancy. We...

Problems of quantitative investigation of intracellular diffusion and compartmentation of metabolites are analyzed. Principal controversies in recently published analyses of these problems for the living cells are discussed. It is shown that the formal theoretical analysis of diffusion of metabolites based on Fick's equation and using fixed diffusi...

Emerging evidence suggests that dietary phytoestrogens can have beneficial effects on obesity and diabetes, although their mode of action is not known. Here, we investigate the mechanisms mediating the action of dietary phytoestrogens on lipid and glucose metabolism in rodents. Male CD-1 mice were fed from conception to adulthood with either a high...

Hyperammonemic disorders in pediatric patients lead to poorly understood irreversible effects on the developing brain that may be life-threatening. We showed previously that some of these NH4+-induced irreversible effects might be due to impairment of axonal growth that can be protected under ammonium exposure by creatine co-treatment. The aim of t...

A histidine residue with a pKa of 7 has been inferred to act as a general acid-base catalyst for the reaction of creatine kinase (CK), catalyzing the reversible phosphorylation of creatine by ATP. The chicken sarcomeric muscle mitochondrial isoenzyme Mib-CK contains several histidine residues that are conserved throughout the family of creatine kin...

Creatine kinase (CK) has been postulated to consist of two flexibly hinged domains. A previously demonstrated protease-sensitive site in M-CK (Morris & Jackson, 1991) has directed our attempts to dissect mitochondrial CK (Mi-CK) into two protein fragments encompassing amino acids [1-167] and [168-380]. When expressed separately in Escherichia coli,...

OBJECTIVE—Emerging evidence suggests that dietary phy-toestrogens can have beneficial effects on obesity and diabetes, although their mode of action is not known. Here, we investigate the mechanisms mediating the action of dietary phytoestrogens on lipid and glucose metabolism in rodents. RESEARCH DESIGN AND METHODS—Male CD-1 mice were fed from con...

The creatine kinase (CK) system is essential for cellular energetics in tissues or cells with high and fluctuating energy requirements. Creatine itself is known to protect cells from stress-induced injury. By using an siRNA approach to silence the CK isoenzymes in human keratinocyte HaCaT cells, expressing low levels of cytoplasmic CK and high leve...

Doxorubicin (DXR) belongs to the most efficient anticancer drugs. However, its use is limited by a risk of cardiotoxicity, which is not completely understood. Recently, we have shown that DXR impairs essential properties of purified mitochondrial creatine kinase (MtCK), with cardiac isoenzyme (sMtCK) being particularly sensitive. In this study we a...

Intracellular sensors of cellular energy and nutrient status are emerging as key players in the regulation of cell metabolism in health and disease. AMP-activated protein kinase (AMPK) participates in the control of cellular and whole-body energy balance by its exquisite sensitivity to AMP. AMPK is thus able to sense and to react to an increasing A...

IntroductionCardiac Energetics: The Frank-Starling Law and Its Metabolic AspectsExcitation–Contraction Coupling and Calcium Metabolism Excitation–Contraction CouplingThe Mitochondrial Calcium CycleLength-dependent Activation of Contractile SystemIntegrated Phosphotransfer and Signaling Networks in Regulation of Cellular Energy Homeostasis Evidence...

Adenosine 5'-monophosphate activated protein kinase (AMPK) is a key regulator of cellular and systemic energy homeostasis conserved in eucaryotic cells from archaezoa to man [1]. Decreased activity of AMPK is found in patients with type 2 diabetes (T2D) and obesity. There is now strong experimental evidence that the controlled direct pharmacologica...

Putative targets of AMP-activated protein kinase (AMPK) were identified in brain extracts using a new proteomic screening method. Following the identification of 26 new potential downstream targets by mass spectrometry, 14 highly purified proteins were tested by direct incubation with AMPK in vitro, thereby confirming 12 of these. The multidimensio...

The tumour suppressor LKB1 plays a critical role in cell proliferation, polarity and energy metabolism. LKB1 is a Ser/Thr protein kinase that is associated with STRAD and MO25 in vivo. Here, we describe the individual expression of the three components of the LKB1 complex using monocistronic vectors and their co-expression using tricistronic vector...

Creatine is a substrate of cytosolic and mitochondrial creatine kinases. Its supplementation augments cellular levels of creatine and phosphocreatine, the rate of ATP resynthesis, and improves the function of the creatine kinase energy shuttle. High cytoplasmatic total creatine levels have been reported to be neuroprotective by inhibiting apoptosis...

In the present study, we investigated the expression pattern of cytosolic brain specific-BB-CK and ubiquitous mitochondrial-creatine kinases (uMt-CK) in developing human spinal cord. Consequently, we studied the effects of creatine treatment on cultured fetal human spinal cord tissue. We found that both CK isoforms were expressed in fetal spinal co...

Creatine kinase (CK) isoenzymes are essential for storing, buffering and intracellular transport of "energy-rich" phosphate compounds in tissues with fluctuating high energy demand such as muscle, brain and other tissues and cells where CK is expressed. In brain and many non-muscle cells, ubiquitous cytosolic "brain-type" BB-CK and ubiquitous mitoc...

Stroke leads to energy failure and subsequent neuronal cell loss. Creatine and phosphocreatine constitute a cellular energy buffering and transport system, and dietary creatine supplementation was shown to protect neurons in several models of neurodegeneration. Although creatine has recently been found to reduce infarct size after cerebral ischemia...

When stimulated strongly, a hair cell's mechanically sensitive hair bundle may consume ATP too rapidly for replenishment by diffusion. To provide a broad view of the bundle's protein complement, including those proteins participating in energy metabolism, we used shotgun mass spectrometry methods to identify proteins of purified chicken vestibular...

Reversible phosphorylation of proteins plays an important role in many cellular processes. To investigate the functions of kinases and their substrates in vivo and in vitro—for example, production of phospho-specific antibodies or generation of phospho-site mutants—the precise identification of phosphorylation sites is mandatory.

We show in this study that mitochondrial creatine kinase promotes segregation and clustering of cardiolipin in mixed membranes, a phenomenon that has been proposed to occur at contact sites in the mitochondria. This property of mitochondrial creatine kinase is dependent on the native octameric structure of the protein and does not occur after heat-...

This study provides evidence of a novel function for mitochondrial creatine kinase (MtCK) and nucleoside diphosphate kinase (NDPK-D). Both are basic peripheral membrane proteins with symmetrical homo-oligomeric structure, which in the case of MtCK was already shown to allow crossbridging of lipid bilayers. Here, different lipid dilution assays clea...

Collagen. Statistical analysis showed there were significant interaction effects of both Cr*medium and donor*medium. This means that the effects of Cr were dependent on the media used, and the donors respond individually to the media used. Addition of either 1 mM pyr or 49.5 mM mannitol to glc 5.5 seemed to reduce the values of celluar. collagen pr...