At extreme altitude (>5,000 – 5,500 m), sustained hypoxia threatens human function and survival, and is associated with marked involuntary weight loss (cachexia). This seems to be a coordinated response: appetite and protein synthesis are suppressed, and muscle catabolism promoted. We hypothesise that, rather than simply being pathophysiological dysregulation, this cachexia is protective. Ketone bodies, synthesised during relative starvation, protect tissues such as the brain from reduced oxygen availability by mechanisms including the reduced generation of reactive oxygen species, improved (...) mitochondrial efficiency and activation of the ATP‐sensitive potassium (KATP) channel. Amino acids released from skeletal muscle also protect cells from hypoxia, and may interact synergistically with ketones to offer added protection. We thus propose that weight loss in hypoxia is an adaptive response: the amino acids and ketone bodies made available act not only as metabolic substrates, but as metabolic modulators, protecting cells from the hypoxic challenge.Also watch the Video Abstract. (shrink)

Bacteria have evolved advanced strategies for surviving during nutritional stress, including expression of specialized enzyme systems that allow them to grow on unusual nutrient sources. Inorganic phosphate (Pi) is limiting in most ecosystems, hence organisms have developed a sophisticated, enzymatic machinery known as carbon‐phosphorus (C‐P) lyase, allowing them to extract phosphate from a wide range of phosphonate compounds. These are characterized by a stable covalent bond between carbon and phosphorus making them very hard to break down. Despite the challenges involved (...) in both synthesizing and catabolizing phosphonates, they are widespread in nature. The enzymes required for the bacterial C‐P lyase pathway have been identified and for the most part structurally characterized. Nevertheless, the mechanistic principles governing breakdown of phosphonate compounds remain enigmatic. In this review, an overview of the C‐P lyase pathway is provided and structural aspects of the involved enzyme complexes are discussed with a special emphasis on the role of ATP‐binding cassette (ABC) proteins. (shrink)

Bacteria have evolved advanced strategies for surviving during nutritional stress, including expression of specialized enzyme systems that allow them to grow on unusual nutrient sources. Inorganic phosphate (Pi) is limiting in most ecosystems, hence organisms have developed a sophisticated, enzymatic machinery known as carbon‐phosphorus (C‐P) lyase, allowing them to extract phosphate from a wide range of phosphonate compounds. These are characterized by a stable covalent bond between carbon and phosphorus making them very hard to break down. Despite the challenges involved (...) in both synthesizing and catabolizing phosphonates, they are widespread in nature. The enzymes required for the bacterial C‐P lyase pathway have been identified and for the most part structurally characterized. Nevertheless, the mechanistic principles governing breakdown of phosphonate compounds remain enigmatic. In this review, an overview of the C‐P lyase pathway is provided and structural aspects of the involved enzyme complexes are discussed with a special emphasis on the role of ATP‐binding cassette (ABC) proteins. (shrink)

The standard representation of the Central Dogma (CD) of Molecular Biology conspicuously ignores metabolism. However, both the metabolites and the biochemical fluxes behind any biological phenomenon are encrypted in the DNA sequence. Metabolism constrains and even changes the information flow when the DNA‐encoded instructions conflict with the homeostasis of the biochemical network. Inspection of adaptive virulence programs and emergence of xenobiotic‐biodegradation pathways in environmental bacteria suggest that their main evolutionary drive is the expansion of their metabolic networks towards new chemical (...) landscapes rather than perpetuation and spreading of their DNA sequences. Faulty enzymatic reactions on suboptimal substrates often produce reactive oxygen species (ROS), a process that fosters DNA diversification and ultimately couples catabolism of the new chemicals to growth. All this calls for a revision of the CD in which metabolism (rather than DNA) has the leading role. (shrink)

Intermediary metabolism molecules are orchestrated into logical pathways stemming from history (L-amino acids, D-sugars) and dynamic constraints (hydrolysis of pyrophosphate or amide groups is the driving force of anabolism). Beside essential metabolites, numerous variants derive from programmed or accidental changes. Broken down, variants enter standard pathways, producing further variants. Macromolecule modification alters enzyme reactions specificity. Metabolism conform thermodynamic laws, precluding strict accuracy. Hence, for each regular pathway, a wealth of variants inputs and produces metabolites that are similar to but not (...) the exact replicas of core metabolites. As corollary, a shadow, paralogous metabolism, is associated to standard metabolism. We focus on a logic of paralogous metabolism based on diversion of the core metabolic mimics into pathways where they are modified to minimize their input in the core pathways where they create havoc. We propose that a significant proportion of paralogues of well-characterized enzymes have evolved as the natural way to cope with paralogous metabolites. A second type of denouement uses a process where protecting/deprotecting unwanted metabolites - conceptually similar to the procedure used in the laboratory of an organic chemist - is used to enter a completely new catabolic pathway. (shrink)

One of the near-to-invariant hallmarks of early apoptosis (programmed cell death) is mitochondrial membrane permeabilization (MMP). It appears that mitochondria fulfill a dual role during the apoptotic process. On the one hand, they integrate multiple different pro-apoptotic signal transducing cascades into a common pathway initiated by MMP. On the other hand, they coordinate the catabolic reactions accompanying late apoptosis by releasing soluble proteins that are normally sequestered within the intermembrane space. In a recent study,(1) Li et al. described a nuclear (...) transcription factor (Nur77/TR1/NGFI-B) that can translocate to mitochondrial membranes to induce MMP. Moreover, two groups(2,3) identified a novel intermembrane protein (Smac/DIABLO) that specifically neutralizes the inhibitor of apoptosis (IAP) proteins, thereby facilitating the activation of caspases, a class of proteases activated during apoptosis. These findings refine our knowledge how MMP connects to the cellular suicide machinery. BioEssays 23:111–115, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Studies of the regulation of heme oxygenase by synthetic metalloporphyrins reveal that within this group of compounds there exist both inducers and inhibitors of the synthesis of this enzyme or of its catalytic function. The ability of metalloporphyrins to alter heme catabolism is of considerable experimental and clinical interest since such alterations may have consequences for other aspects of heme homeostasis, including its synthesis and its function in the form of cytochrome(s) P‐450. Examples of the metabolic effects – and (...) their potential clinical and pharmacological consequences – produced by two synthetic metalloporphyrins, Sn‐protoporphyrin and Co‐protoporphyrin, are discussed. (shrink)

Maintenance of skeletal muscle mass and strength throughout life is crucial for heathy living and longevity. Several signaling pathways have been implicated in the regulation of skeletal muscle mass in adults. TGF‐β‐activated kinase 1 (TAK1) is a key protein, which coordinates the activation of multiple signaling pathways. Recently, it was discovered that TAK1 is essential for the maintenance of skeletal muscle mass and myofiber hypertrophy following mechanical overload. Forced activation of TAK1 in skeletal muscle causes hypertrophy and attenuates denervation‐induced muscle (...) atrophy. TAK1‐mediated signaling in skeletal muscle promotes protein synthesis, redox homeostasis, mitochondrial health, and integrity of neuromuscular junctions. In this article, we have reviewed the role and potential mechanisms through which TAK1 regulates skeletal muscle mass and growth. We have also proposed future areas of research that could be instrumental in exploring TAK1 as therapeutic target for improving muscle mass in various catabolic conditions and diseases. (shrink)

In the bacterium Escherichia coli, the AraC protein positively and negatively regulates expression of the proteins required for the uptake and catabolism of the sugar L‐arabinose. This essay describes how work from my laboratory on this system spanning more than thirty years has aided our understanding of positive regulation, revealed DNA looping (a mechanism that explains many action‐at‐a‐distance phenomena) and, more recently, has uncovered the mechanism by which arabinose shifts AraC from a state where it prefers to bind to (...) two well‐separated DNA half‐sites and form a DNA loop to a state where it binds to two adjacent half‐sites and activates transcription. This work required learning how to assay, purify, and work with a protein possessing highly uncooperative biochemical properties. Present work is focussed on understanding arabinose‐responsive mechanism in atomic detail and is also directed towards understanding protein structure and function well enough to be able to engineer the allosteric mechanism seen in AraC onto other proteins. BioEssays 25:274–282, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The origin of the eukaryotic cell nucleus and the selective forces that drove its evolution remain unknown and are a matter of controversy. Autogenous models state that both the nucleus and endoplasmic reticulum (ER) derived from the invagination of the plasma membrane, but most of them do not advance clear selective forces for this process. Alternative models proposing an endosymbiotic origin of the nucleus fail to provide a pathway fully compatible with our knowledge of cell biology. We propose here an (...) evolutionary scenario that reconciles both an ancestral endosymbiotic origin of the eukaryotic nucleus (endosymbiosis of a methanogenic archaeon within a fermentative myxobacterium) with an autogenous generation of the contemporary nuclear membrane and ER from the bacterial membrane. We specifically state two selective forces that operated sequentially during its evolution: (1) metabolic compartmentation to avoid deleterious co‐existence of anabolic (autotrophic synthesis by the methanogen) and catabolic (fermentation by the myxobacterium) pathways in the cell, and (2) avoidance of aberrant protein synthesis due to intron spreading in the ancient archaeal genome following mitochondrial acquisition and loss of methanogenesis. BioEssays 28: 525–533, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Observed biological growth curves generally are sigmoid in appearance. It is common practice to fit such data with either a Verhulst logistic or a Gompertz curve. This paper critically considers the conceptual bases underlying these descriptive models.The logistic model was developed by Verhulst to accommodate the common sense observation that populations cannot keep growing indefinitely. A justification for using the same equation to describe the growth of individuals, based on considerations from chemical kinetics (autocatalysis of a monomolecular reaction), was put (...) forward by Richardson, but met with heavy criticism as a result of his erroneous derivation of the basic equation (Snell, 1929). It errs on the side of over-simplicity (Priestley & Pearsall, 1922). Von Bertalanffy (1957) subsequently based a justification on the assumption that, as a first approximation, the rates of catabolism and anabolism may be assumed to be proportional to weight and power (still vacant places, between the maximal possible and the already accumulated population sizes. This point of view was fiercely challenged by Nicholson (1933), Milne (1962), Smith (1954) and Rubinov (1973). And indeed, what is meant by vacant places has never become entirely clear. Finally Lotka (1925) devised a third leading approach by just truncating a Taylor expansion around zero of the differential law for autonomous growth after the second degree term. (shrink)

AMP‐activated protein kinase (AMPK) is an evolutionarily conserved cellular switch that activates catabolic pathways and turns off anabolic processes. In this way, AMPK activation can restore the perturbation of cellular energy levels. In physiological situations, AMPK senses energy deficiency (in the form of an increased AMP/ATP ratio), but it is also activated by metabolic insults, such as glucose or oxygen deprivation. Metformin, one of the most widely prescribed anti‐diabetic drugs, exerts its actions by AMPK activation. However, while the functions of (...) AMPK as a metabolic regulator are fairly well understood, its actions in neuronal cells only recently gained attention. This review will discuss newly emerged functions of AMPK in neuroprotection and neurodegeneration. Additionally, recent views on the role of AMPK in autophagy, an important catabolic process that is also involved in neurodegeneration and cancer, will be highlighted. (shrink)

Molecular imprints of organisms serving as both the agents and the products of the underlying sign activities are quantum mechanical in their origins. In particular, molecules in any reaction networks constituting a biological organism are semiotic or context-dependent in the sense that their activities reside within the proper coordination of the entire networks. The origin of life could have been related to a specific aspect of molecular semiotics, especially in the transition from molecules as the physical symbols of material units (...) to molecules as the semiotic signs having the capacity of pointing to something else other than the molecules themselves. Quantum mechanical underpinning of the molecular imprints leading to the emergence of life is in the appraisal of the material capacities of both coherent assimilation and decoherent dissociation already latent in the imprints. One empirical evidence suggesting the likelihood of both coherent assimilation and decoherent dissociation in prebiotic settings could have been found in synthetic chemical reactions running in hydrothermal circulation of seawater through hot vents in the Haedean ocean on the primitive Earth. (shrink)

A model is proposed which implicates molecular recognition systems as the major controlling factors in life cycle expression. It is envisaged that such systems are important in immune functioning and catabolic, metabolic molecule recognition at both inter- and intea-cellular level. These recognition systems have the following characteristics: Specific recognition molecules , e.g. vertebrate antibodies, invertebrate agglutinins and plant agglutinins may recognise specific substances, e.g. antigens, catabolic and metabolic molecules. The range of possible recognisable substances is very wide and variable. The (...) recognisers may themselves be recognised by other recognisers. Recognisers are usually produced in large amounts only on presentation of the appropriate recognisable molecule. The progressive introduction of new recognisable molecules increases the recogniser interaction, this interaction causing depression of some recogniser types and facilitation of other types among which may be recognisers specific for self components . Low juvenile viability is associated with a restricted range of available recognisers, high adult viability with increasing recogniser range and some auto-immunity/immune depression, senescence with a wide range of available recognisers and extensive auto-immunity/immune depression.Life cycle patterns and their control are discussed. It is suggested control mechanisms may include: Dietary restriction and in some periods complete nutritional abstinence. Specific recogniser depression, genes implicated here are the various antigens found on cell surfaces, in the serum and in various body fluids of vertebrates, e.g. ABO, MNSs, P, Rh, Le and other blood groups, the ABO and Le secretor antigens and the HL-A antigens. In addition the immune response and mixed lymphocyte culture loci are implicated. Finally life cycle control is discussed with relation to sexual selection. (shrink)

A decade ago I postulated that ROS formation in mitochondria was influenced by different FADH2/NADH (F/N) ratios of catabolic substrates. Thus, fatty acid oxidation (FAO) would give higher ROS formation than glucose oxidation. Both the emergence of peroxisomes and neurons not using FAO, could be explained thus. ROS formation in NADH:ubiquinone oxidoreductase (Complex I) comes about by reverse electron transport (RET) due to high QH2 levels, and scarcity of its electron‐acceptor (Q) during FAO. The then new, unexpected, finding of an (...) FAO enzyme, ACAD9, being involved in complex I biogenesis, hinted at connections in line with the hypothesis. Recent findings about ACAD9's role in regulation of respiration fit with predictions the model makes: cementing connections between ROS production and F/N ratios. I describe how ACAD9 might be central to reversing the oxidative damage in complex I resulting from FAO. This seems to involve two distinct, but intimately connected, ACAD9 characteristics: (i) its upregulation of complex I biogenesis, and (ii) releasing FADH2, with possible conversion into FMN, the crucial prosthetic group of complex I. Also see the video abstract here: https://youtu.be/N7AT_HBNumg. (shrink)