On the origin of intracellular compartmentation and organized metabolic systems

The history of the development of the ideas and research of organized metabolic systems during last three decades is shortly reviewed. The cell cytoplasm is crowded with solutes, soluble macromolecules such as enzymes, nucleic acids, structural proteins and membranes. The high protein density within the large compartments of the cells predominantly determines the major characteristics of cellular environment such as viscosity, diffusion and inhomogeneity. The fact that the solvent viscosity of cytoplasm is not substantially different from the water is explained by intracellular structural heterogeneity: the intrinsic macromolecular density is relatively low within the interstitial voids in the cell because many soluble enzymes are apparently integral parts of the insoluble cytomatrix and are not distributed homogeneously. The molecular crowding and sieving restrict the mobility of very large solutes, binding severely restrict the mobility of smaller solutes. One of consequence of molecular crowding and hindered diffusion is the need to compartmentalize metabolic pathway to overcome diffusive barriers. Although the movement of small molecules is slowed down in the cytoplasm, the metabolism can successfully proceed and even be facilitated by metabolite channeling which directly transfers the intermediate from one enzyme to an adjacent enzyme without the need of free aqueous-phase diffusion. The enhanced probability for intermediates to be transferred from one active site to the other by sequential enzymes requires stable or transient interactions of the relevant enzymes, which associate physically in non-dissociable, static multienzyme complexes--metabolones, particles containing enzymes of a part or whole metabolic systems. Therefore, within the living cell the metabolism depends on the structural organization of enzymes forming microcompartments. Since cells contain many compartments and microenvironments, the measurement of the concentration of metabolites in whole cells or tissues gives an average cellular concentration and not that which is actually sensed by the active site of a specific enzyme. Thus, the microcompartmentation could provide a mechanism which can control metabolic pathways. Independently and in parallel to the developments described above, the ideas of compartmentation came into existence from the necessity to explain important physiological phenomena, in particular in heart research and in cardiac electrophysiology. These phenomena demonstrated the physiological importance of the biophysical and biochemical mechanisms described in this review.     

On the mechanistic origin of damped oscillations in biochemical reaction systems

A generalized reaction scheme for the kinetic interaction of two reactants in a metabolic pathway has been examined in order to establish what minimal mechanistic patterns are required to support a damped oscillatory transient-state kinetic behaviour of such a two-component system when operating near a steady state. All potentially oscillating sub-systems inherent in this scheme are listed and briefly characterized. The list includes several mechanistic patterns that may be frequently encountered in biological system (e.g. involving feedback inhibition, feed-forward activation, substrate inhibition or product activation), but also draw attention to some hitherto unforeseen mechanisms by which the kinetic interaction of two metabolites may trigger damped oscillations. The results can be used to identify possible sources of oscillations in metabolic pathways without detailed knowledge about the explicit rate equations that apply.     

On rate-sensitive chemoreceptor systems and the origin of the immune response.

The properties of cellular chemoreceptor systems are explored, from the viewpoint that they are elements involved in the functioning of larger physiological homeostatic mechanisms. It is shown that the necessity to integrate a chemoreceptor into such a homeostat, in such a way that an adaptive physiological response is generated, places strong constraints on the properties of the chemoreceptor. The consequences of these constraints are then explored in the context of chemoreceptors which are rate-sensitive. It is argued that the features of such rate-sensitive chemoreceptors automatically possess many of the basic features of an immune mechanism, such as tolerance inducibility, memory, the biosynthesis of antibody-like material, cellular proliferation and the possibility of co-operative inter-action between cells. Some suggestions for the evolution of an immune system from an original rate-sensitive chemodetector are proposed.     

Teaching the origin of the first living systems

The most fundamental of questions in biology, namely that of the origin of living systems, is being lost to teaching and a new technique to rekindle interest in it must be found. This paper presents a novel idea of teaching a scientific concept using a poem, which describes the major perspectives on the origins of living systems, as the medium of instruction. All of the major schools of thought — chemical evolution, DNA vs. RNA, protocell formation, coacervates, panspermia and special creation — are discussed. The aim of the paper is not to be a definitive review on the origin of living systems, but rather to be a focal point on which to hinge further discussion.     

On the origin of plastids

The buoyant density in CsCl of ribosomes from chloroplasts of the green algaChlorella pyrenoidosa and two species of higher plants,Pisum sativum andChenopodium album, has been studied. From the relative protein content it was calculated that 70S ribosomes from chloroplasts are much smaller than 80S cytoplasmic ribosomes (3.0–3.1×10⁶ and 4.0×10⁶ daltons) and slightly larger than 70S ribosomes from abcteriaE. coli 2.5×10⁶ daltons). Chloroplast ribosomes from pea seedlings were analyzed by two-dimensional polyacrylamide gel electrophoresis. They appear to contain 71 proteins. This indicates that chloroplast ribosomes contain a larger number of proteins than do the ribosomes fromE. coli and other species of Enterobacteriaceae. Further study will permit a probable evaluation of the validity of Mereschkowsky's hypothesis that the photosynthetic plastids of eukaryotic plant cells are the evolutionary descendants of endosymbiotic blue-green algae.     

On the origin of feathers

The appearance of feathers defines the appearance of birds. A number of changes defined, preceded or accompanied the event. The changes were hierarchical in nature and included revolutions in genomic organization (i.e., HOX and the feather keratin genes), protein sequence and shape, the large scale organization of proteins into filaments, and in the geometry of the cells and their roles in the follicle. Changes at each of these levels differ or produced different products than found in its analog in reptiles. They are essentially unique to birds and produced an evolutionary novelty. I used analysis of extant structure and information on development to reconstruct key events in the evolution of feathers. The ancestral reptilian epidermal structure, while probably a scale or tubercles, is still unidentified. The structural genes of feather proteins (φ-keratin) are tandem repeats probably assembled from pre-existing exons. They are unlike the alpha-keratin of vertebrate soft epidermis. Amino-acid composition, shape, and behavior of feather keratins are unique among vertebrates. The 3-dimensional organization of the follicle and the developmental processes are also unique. Although we lack a complete understanding of the appearance and early role of feathers, they are clearly the results of novel events.     

On the origin of photophosphorylation

A model based on quinol phosphates is proposed for the origin of photophosphorylation. This model is divided into three time periods. In the early period, when the primitive earth was under reducing conditions, quinol phosphates were produced through quinol radical intermediates formed by the activation of hydroquinones with ultraviolet light. Phosphorylation of a number of acceptor molecules including inorganic orthophosphate and adenosine diphosphate occurred when quinol phosphate was oxidized by Fe⁺³ or a water soluble iron-sulfur complex. After the appearance of a rudimentary ozone layer (middle period), ultraviolet light was no longer an important factor in primordial chemistry. Quinol phosphates were then produced by visible light activation of porphyrin-quinone charge transfer complexes. In the presence of light, electrons from H₂S, H₂ and several reduced organic compounds were transfered through the porphyrin to quinone yielding the quinol radical. Again, quinol phosphate was produced from breakdown of the free radical. Phosphorylation of a number of acceptor molecules was achieved when quinol phosphates were oxidized by the iron-sulfur complexes. Evolutionary pressure to increase the efficiency of these reactions resulted in the electron donor-porphyrin-quinone-iron-sulfur complex becoming more lipophilic and thus associated with the protomembrane of the evolving protocell. In the late period the protomembrane became more sophisticated and quinone was replaced as the primary electron acceptor in the photoprocess by one of the iron-sulfur complexes originally present as oxidizing agents for the quinol phosphates. Quinones eventually lost their role as phosphorylating agents and became only electron and proton shuttles in the evolving electron transport chain. The protocell evolved the ability to use water as the electron donor as the relative roles of iron and quinone in the photoprocess switched.     

On the origin of life

On the basis of the recently proposed new fundamental equation of mathematical biophysics, a suggestion is made for a theory of the formation of a primitive cell from nonliving material. The discussion includes a suggestion for a quantitative formulation of the degree of biological organization. It is shown that according to the fundamental equation of mathematical biophysics, organization of the nonliving material may spontaneously increase under certain conditions, leading to a formation of a primitive organism. This process however, is a very slow one, requiring time intervals of several years or even decades. This may account for the failure in observing or artificially producing spontaneous generation.     

On the origin of prokaryotes

It has been a tacit assumption of evolutionary theory that the closest surviving relatives of the first cellular organisms are to be found among prokaryotes. This paper draws attention to the fact that many stages of evolution appear to have been accompanied by physical loss of superfluous DNA. It is postulated that the genomes of prokaryotes—where almost every gene is represented by one copy only—represent the results of this process carried to its extreme. On this basis certain features of very early evolution which have been eliminated from prokaryotes may survive in eukaryotes. If correct, the hypothesis would require a careful re-evaluation of the assumptions underlying use of some sequence data to construct phylogenetic trees.     

On the origin of differentiation

Following the origin of multicellularity in many groups of primitive organisms there evolved more than one cell type. It has been assumed that this early differentiation is related to size — the larger the organism the more cell types. Here two very different kinds of organisms are considered: the volvocine algae that become multicellular by growth, and the cellular slime moulds that become multicellular by aggregation. In both cases there are species that have only one cell type and others that have two. It has been possible to show that there is a perfect correlation with size: the forms with two cell types are significantly larger than those with one. Also in both groups there are forms of intermediate size that will vary from one to two cell types depending on the size of the individuals, suggesting a form of quorum sensing. These observations reinforce the view that size plays a critical role in influencing the degree of differentiation.     

On the origin of neurons

A report on the conference 'Neurogenesis 2007', Tokyo, Japan, 15-16 May 2007.