Q J Med 2001; 94: 45-48
© 2001 Association of Physicians
Commentary |
A molecular biological basis for the nutritional and pharmacological benefits of dietary plants
From the Gastrointestinal Unit, Department of Medicine, University of Edinburgh, Western General Hospital Trust, Edinburgh, UK
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Summary |
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 Top Summary IntroductionSecondary plant metabolitesEvolution, genes and proteinsMetabolic regulationConclusionReferences |
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Individuals who regularly eat fruit and vegetables gain protection against a number of diseases. These advantages are usually ascribed to the rich vitamin, antioxidant and dietary fibre content of fruit and vegetables. However, clinical trials testing whether these nutrients are protective against specific diseases have been less consistent. The secondary metabolites of plant metabolism, particularly those from the terpenoid and phenolic families, could provide some of this health protection, through regulatory effects on the functional domains of ancient conserved proteins and DNA regions common to both plants and mammals. Small-molecular-mass molecules can regulate gene expression in a variety of ways, e.g. targeting DNA sequences, inducing gene expression and binding to protein-regulating sites. Secondary plant metabolites may also modulate the function of transmembrane channel receptors and enzymes.
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Introduction |
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TopSummaryIntroductionSecondary plant metabolitesEvolution, genes and proteinsMetabolic regulationConclusionReferences |
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Individuals who regularly eat fruit and vegetables appear to gain protection against a number of diseases. There is considerable interest in making maximum informed use of these widely available natural products. The advantages are usually ascribed to the rich vitamin, antioxidant and dietary fibre content of fruit and vegetables. However, clinical trials of individual nutrients in specified disease situations have been disappointing.1 Herbal medicine uses many important remedies of plant origin. It is possible that as yet unidentified constituents of fruit and vegetables are health-promoting. The various parts of plants that are consumed as food include: flowers (e.g. cauliflower); fruits and seeds; leaves (e.g. cabbage); stems (asparagus); petiole (e.g. rhubarb); underground tubers (e.g. potato) and roots (e.g. carrot). Four-fifths of known natural products are of plant origin, and can be classified as primary or secondary metabolites. Plants contain an array of secondary plant substances, varying quantitatively and qualitatively with the plant anatomy. Primary metabolites (e.g. amino acids, sugars, fatty acids) are fundamental to organisms through all the major biological kingdoms and are involved in metabolism, growth, maintenance and survival. Secondary metabolites are synthesized in plants from a few key intermediates of primary metabolism, and include non-protein amino acids, alkaloids, phenols and isoprenoids.2
It could be that secondary metabolites of plant metabolism provide health protection, through regulatory effects by secondary metabolites on functional domains of proteins common to both plants and mammals.3
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Secondary plant metabolites |
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TopSummaryIntroductionSecondary plant metabolitesEvolution, genes and proteinsMetabolic regulationConclusionReferences |
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Secondary plant metabolites have traditionally been regarded as toxic and protective against predators, or acting as insect attractants. These chemicals have a role as protection in the struggle with the animal world.4 They (i) are chemically diverse natural products, not synthesized outside the plant kingdom; (ii) are accessories to primary metabolites; (iii) are not excreted and accumulate in plants, and act as hormones and in the plant defence mechanisms; and, (iv) can have both toxicological, behavioural and attractant effects on many different species, including interesting properties in the mammalian central nervous system as stimulants or sedatives or by acting on the cardiovascular system.5
Alkaloids are structurally the most diverse class of secondary metabolites, ranging from simple structures (e.g. coniine) to exceedingly complex. They are classified by the amino acid or derivatives from which they are synthesized: ornithine and lysine, phenylalanine and tyrosine, tryptophan or anthranilic acid, nicotinic acid, polyketides or terpenoids. Phenolics are aromatic compounds with hydroxyl substitutions. The parent compound is phenol, but most are more complex polyphenolic compounds, classified by the number of carbon atoms in the basic skeleton. Their derived classes have one, two or three side-chains e.g. salicylic acid, p-hydroxyphenylacetic acid, hydroxycinnamic acid and caffeic acids or substituted phenolic terpenoids, e.g. 
1-tetrahydrocannibol.
Terpenoids are formed from five-carbon building units, resulting in compounds with C5, C10, C15, and C20 up to C40 skeletons. Steroids are classified separately. Mevalonic acid, a derivative of acetyl-CoA, is the precursor of all terpenoids, sterols and steroids.3
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Evolution, genes and proteins |
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TopSummaryIntroductionSecondary plant metabolitesEvolution, genes and proteinsMetabolic regulationConclusionReferences |
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The genome projects mapping the genetic structure of humans, yeasts6and plants7 now allow comparisons and analysis of basic and cellular mechanisms common to eukaryotes. A unifying theory of shared evolutionary ancestry is that related organisms, including mammals and plants, possess conserved genes and proteins of similar function, which contain sequences which are wholly or partially similar. The term homologous applies to sequences or residues in encoded macromolecules which have the same or similar residues at corresponding positions. In proteins, this implies a common evolutionary origin. Specifically, the designation homologous requires similarity of gene structure, and not merely a similarity of protein structure or proteins from different species having similar functions.8 Similar function by proteins in differing kingdoms does not necessarily imply conservation.9
The term ‘conserved’ means an invariance in corresponding residues or sequences of encoded macromolecules, e.g. proteins obtained from genetically different species. Macromolecules with a high degree of invariance of their primary structure are said to be highly conserved. Conserved and homologous proteins from different species contain regions that retain the same structural fold, and also regions where the folds differ. For pairs of distantly-related proteins (residue identity 
20%) the regions with the same homologous fold may form less than half of the molecule. Homologous proteins include the globins, cytochromes, serine proteases, dihydrofolate reductase, Cu-electron transport proteins, sulphydryl protease, lysozyme, and immunoglobulin domains.10,11
The conserved proteins found in species which extend over the evolutionary tree are called ancient conserved proteins (ACP). The conservation may be confined to the functional region of the proteins in what is known as the ancient conserved region (ACR). Over long periods of evolution, the remaining less constrained portions of proteins have significantly diverged.8
The amino-acid sequence of 57 different enzymes has been used to determine the divergence times during evolution of the major biological kingdoms. There are unequal rates of change over long time periods for the different evolutionary lineages. Fungi and animals appear to have shared a common ancestor more recently than did either with plants. On the whole however, plant protein sequences are more like those of animals than of fungi.8 Some 900 ancient conserved regions (ACRs) may account for most of the similarities observed between different phyla.12 There is conservation of the determinants of cell physiology from genes13 control of gene expression14 and repair15 and proteins involved in metabolic processes. The range of conserved ACPs and ACRs extends from ribosomal proteins,16 signal transduction,17 the electron transport chain, transport proteins for ions and amino acids,18 cell surface receptors, and P450 genes, to the large enzyme families.19
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Metabolic regulation |
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TopSummaryIntroductionSecondary plant metabolitesEvolution, genes and proteinsMetabolic regulationConclusionReferences |
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Biological functions may be regulated by coarse and fine control systems. Coarse control requires regulatory genes which orchestrate the co-ordinated expression (transcription), of structural genes coding for biosynthetic enzymes, the control of catabolic reactions or the secretion and intracellular targeting of a compound. Fine control involves post-translational mechanisms that are on/off switches for biosynthetic processes, but which also ensure that the synthetic rate is consistent with the immediate demands of a cell. These include modulation of enzyme activity through protein modification (e.g. protein phosphorylation), feedback regulation through a reaction product or pathway end-product and other kinetic controls which effect the catalytic efficiency of a biosynthetic enzyme. Secondary metabolites in plants regulate function in genes and proteins, some of which are conserved in other phyla, acting in physiological amounts, to be subsequently stored, as plants have no elimination system. The concentrations in the storage organs may increase to high concentrations. Subsequently, when these become available to other organisms for whatever purpose, they will produce responses as in the plant, ranging from the physiological to the therapeutic and even toxic, acting on the ACPs or ACRs common to the plant or recipient organisms.
Plant secondary chemicals have at least two properties: (i) type 1 function, where the plant uses the secondary metabolites to interact with other organisms in a protective or attractive manner (i.e. as a kairomone or allomone); or (ii) type 2 function, where the secondary metabolite acts as an ectocrine (i.e. functioning on the coarse and fine control of biological function in an apparently unrelated species in a similar control system as in the plant), with no immediate benefit to the individual plant.
The secondary metabolites with type 1 properties in general belong to the non-protein amino acids and alkaloid families of chemicals. Secondary metabolites with type 2 characteristics tend to belong to the phenolic and terpenoid families.5
Specific areas where type 2 secondary metabolites may have important functions in human physiology include the following.
Genes governing the APR and ACR
Small-molecular-mass molecules can regulate gene expression in a variety of ways, e.g. targeting DNA sequences,20 inducing gene expression and binding to protein regulating sites.21 Within the plant there are many promotors of gene activity: monoterpenes, abscinic acid, methyl jasmonate, flavonoids, gibberillic acid, okadaic acid and 2,4-dichlorophenoxyacetic acid.22 All of these promote growth in the rat lung, small intestine, liver, renal cortex and increase guanylate cyclase activity. Salicylic acid, a phenolic acid present in plants in the unconjugated, methyl or acetylated form, increases gene expression in both plants and mammalian cell systems.23,24
Mevalonic acid
All cells depend upon sterols and isoprenoids derived from mevalonic acid for growth, differentiation and maintenance of homeostasis. HMG-CoA reductase is central to the synthesis25,26 of sterols and steroids, including the steroid hormones. Dietary type 2 secondary-metabolite modulators of HMG-CoA reductase activity include brassinosteroids.27
Transmembrane channels receptors
A number of plant secondary metabolites modulate transmembrane channel activity in many mammalian tissue receptors, e.g. the opiates, the cardiac glycosides28 and even abscisic acid.29
The kinase family of enzymes
This enzyme family is found in many key biological processes throughout the plant and animal kingdoms. The 14-3-3 family is a good example.19 Kinase family enzymes are activated by specific reactions both in plants and mammals. Protein phosphorylation is a common mechanism by which cellular activity is regulated. The control and modulation of the ACP and ACR forms of kinases may well be controlled by similar mechanisms in plants and human.19
The cytochrome P450 superfamily
The cytochrome P450 family is present in all members of the various kingdoms.30 The widely-distributed haemoprotein system seems to have evolved from a single ancestral protein with diverse physiological functions in development, synthesis and oxidative metabolism.31 Plant materials can alter human P450 activity.32 It is not unreasonable to assume that in a conserved P450 superfamily, a P450 enzyme system which is involved in the synthesis of a chemical in the plant, might in humans be involved in that plant chemical's metabolism and elimination when it is ingested and seen as a noxious foreign compound.
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Conclusion |
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TopSummaryIntroductionSecondary plant metabolitesEvolution, genes and proteinsMetabolic regulationConclusionReferences |
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The health-promoting benefits attributed to dietary fruit and vegetables have yet to be fully explained. This has led to considerable interest and research into the mechanisms of this benefit. The well-demonstrated benefits afforded by vitamins, anti-oxidants and dietary fibre appear to be only part of the contributory benefits, and the remainder of protective mechanism remains frustratingly difficult to identify. Benefits from dietary fruit and vegetables may be gained from plant secondary metabolites acting on genes and the ancient conserved proteins and domains of proteins present in plants and humans. Further insights may be provided by using the new information provided by the genome projects. Genes, ACP and ACR common to plants and mammals could then be used as substrates for plant secondary metabolites in biological systems to facilitate the use of plant secondary metabolites in mammalian systems. Closer collaboration between plant and human research projects could be very productive.
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Notes |
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Address correspondence to Dr M.A. Eastwood, Hill House, North Queensferry, Fife KY11 1JJ.
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References |
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TopSummaryIntroductionSecondary plant metabolitesEvolution, genes and proteinsMetabolic regulationConclusionReferences |
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