Secondary Metabolite

Secondary metabolites (SMs) are generally defined as small organic molecules produced by
an organism that are not essential for their growth, development and reproduction.
From: Biotechnology and Biology of Trichoderma, 2014

Related terms:

Metabolic Pathway, Anabolism, Flavonoid, Lysozyme, Gene Cluster, Nested Gene,

Amino Acids, Infectious Agent, Metabolite, Microorganism

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Scientific Fundamentals of Biotechnology

Sergio Sanchez, Arnold L. Demain, in Comprehensive Biotechnology (Third Edition), 2011

Abstract
Microbial secondary metabolites are low-molecular-mass products of secondary metabolism,
usually produced during the late growth phase (idiophase) of microorganisms. They have
unusual structures and their production arises from intracellular intermediates (amino acids,
sugars, fatty acids, etc.), which are condensed into more complex structures by defined
biochemical pathways. They are not essential for the growth of the producing cultures, but
serve diverse survival functions in nature. They are very important for the human health and
economics of our society. They include antibiotics, antitumor agents, cholesterol-lowering
drugs, immunosuppressants, antihelmintic agents and other antiparasitics, herbicides,
ruminant growth stimulators, agricultural fungicides, bio-insecticides, and others. The most
important secondary metabolites have been the anti-infective drugs and, among these, the β-
lactams are the most important class. Other important classes include the aminoglycosides,
tetracyclines, macrolides, lipopeptides, polyenes, and the echinocandins. Successful microbial
secondary metabolites include many used to combat cancer, such as the anthracycline
doxorubicin and bleomycin. Antitumor agents from plants that have been very useful are
taxol and camptothecin. If modern medicine is to continue in its present form, novel families
of antibiotics and other secondary metabolites must continue to be discovered and enter the
marketplace at regular intervals.

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Scientific Fundamentals of Biotechnology

S. Sanchez, A.L. Demain, in Comprehensive Biotechnology (Second Edition), 2011

1.12.1 Introduction
Of all the traditional products made by fermentation, the most important to human health
are the secondary metabolites (idiolites). These are metabolites which (1) are often produced
in a developmental phase of batch culture (idiophase) subsequent to growth, (2) have no
function in growth, (3) are produced by narrow taxonomic groups of organisms, (4) have
unusual and varied chemical structures, and (5) are often formed as mixtures of closely
related members of a chemical family. In nature, their functions serve the survival of the
strain, but when the producing microorganisms are grown in pure culture, the secondary
metabolites have no such role. Thus, production ability in industry is easily lost by mutation
(‘strain degeneration’). In batch or fed-batch culture, secondary metabolites are produced
usually after growth has slowed down. Their formation is regulated by nutrients, growth rate,
feedback control, enzyme inactivation, and induction. Secondary metabolism is mainly
carried out by plants and microorganisms and is usually strain specific. Secondary
metabolites appear to serve the organisms that produce them as (1) competitive weapons
used against other microorganisms, plants, insects, and large animals; (2) metal transporting
agents; (3) agents of plant–microbe symbiosis and plant growth stimulation; (4) sexual
hormones; and (5) differentiation effectors.
Secondary metabolites have a major effect on the health, nutrition, and economics of our
society. The best known are the antibiotics. This remarkable group of compounds forms a
heterogeneous assemblage of biologically active molecules with different structures and
modes of action. They attack virtually every type of microbial activity such as DNA, RNA, and
protein synthesis, membrane function, electron transport, sporulation, germination, and
many others. Other secondary metabolites are pesticides, pigments, toxins, effectors of
ecological competition and symbiosis, pheromones, enzyme inhibitors, immunomodulating
agents, receptor antagonists and agonists, pesticides, antitumor agents, immunosuppressives,
cholesterol-lowering agents, plant protectants, and growth promotants of animals and plants.
As a result, they have tremendous economic importance. More than 10 000 antibiotics have
been discovered. Most are useless; they are either too toxic or inactive in living organisms to
be used.
Idiolites are typically produced as slightly differing components of a particular chemical
family as a result of low specificity of some enzymes of secondary metabolism, and also of
bottleneck enzymes in the pathway, which lead to the excretion of pathway intermediates
and their transformed products. The ratio of components produced by a strain is often shifted
by the addition of a precursor of one of the components (‘directed biosynthesis’). The main
types of biosynthetic pathways involved are those forming peptides, polyketides, terpenoids,
oligosaccharides, aromatic compounds, and β-lactam rings. Unusual chemical structures
include β-lactam rings, cyclic peptides, depsipeptides containing ‘unnatural’ and nonprotein
amino acids, unusual sugars and nucleosides, unsaturated bonds of polyacetylenes and
polyenes, covalently bound chlorine and bromine; nitro-, nitroso-, nitrilo-, and isonitrilo
groups, hydroxamic acids, diazocompounds, phosphorus as cyclic triesters, phosphonic acids,
phosphinic acids, phosphoramides, 3-, 4-, and 7-membered rings and large rings such as the
37-membered ring system of macrolides, macrotetralides, and arisamycines.
The enormous diversity of secondary metabolites includes 23 000 terpenoids. At least 70
different deoxyhexose sugars are present in natural metabolites. Most of the secondary
metabolites are small (less than 1500 Da) and are produced by nonribosomal systems.
However, there does exist a family of ribosomally derived peptide antibiotics of higher
molecular weight (3000–4000 Da) known as bacteriocins or lantibiotics.
Despite the thousands of secondary metabolites made by microorganisms, they are
synthesized from only a few key precursors in pathways that comprise a relatively small
number of reactions and branch off from primary metabolism at a limited number of points.
Acetyl-coenzyme A (CoA) and propionyl-CoA are the most important precursors in secondary
metabolism, leading to polyketides, terpenes, steroids, and metabolites derived from fatty
acids. Other secondary metabolites are derived from intermediates of the shikimic acid
pathway, the tricarboxylic acid cycle, and from amino acids.

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Aspergillus nidulans☆
B.R. Oakley, in Reference Module in Life Sciences, 2017

Secondary Metabolism
Secondary metabolites are compounds that are not required for the growth or reproduction
of an organism but are produced to confer a selective advantage to the organism. For
example, they may inhibit the growth of organisms with which they compete and, as such,
they often inhibit biologically important processes. Fungal secondary metabolites are a major
source of medically important compounds, from antibiotics such as penicillin to the anti-
cholesterol compound lovastatin. The sequencing of the genomes of A. nidulans and other
species of Aspergillus (Galagan et al., 2005) revealed that they have many genes predicted, on
the basis of sequence, to be involved in secondary metabolism. These genes, moreover, are
clustered together, and it has been demonstrated that individual clusters generally encode
the genes for a single secondary metabolite biosynthetic pathway. These secondary
metabolite biosynthetic clusters are potentially a very important source of medically useful
compounds, but most of the clusters are cryptic – not expressed under normal laboratory
growth conditions. Molecular genetic methods for activating secondary metabolite genes or
entire clusters are being developed, however. This has revealed new A. nidulans secondary
metabolites and is establishing A. nidulans as a model system for studying secondary
metabolism (Bok and Keller, 2004; Andersen et al., 2013; Brakhage, 2013; Chiang et al., 2013;
Yaegashi et al., 2014).

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Secondary Metabolites Production

Javier Barrios-González, in Current Developments in Biotechnology and Bioengineering, 2018

2.2 Carbon Catabolite Repression

Production of SMs is frequently limited due to a negative effect exerted by the carbon source
on the synthesis of many SMs. This regulatory mechanism is termed carbon catabolite
regulation (CCR). There are many examples of enzymes and secondary metabolites regulated
by CCR in bacteria and fungi.
In the filamentous fungus A. chrysogenum, biosynthesis of the β-lactam antibiotic
cephalosporin C is repressed by glucose. In this example, glucose represses biosynthetic
genes pcbC and cefEF by means of the carbon source repressor CRE1 [8]. In Streptomyces, for
example, glucose depresses the formation of many aminoglycoside antibiotics (streptomycin,
kanamycin, istamycin, neomycin) via repression of biosynthetic enzymes [5,9,10].
The strategy to produce SMs subjected to CCR is to use lactose or other slowly metabolized
carbon sources like starch or vegetable oils. An alternative is to maintain glucose at a very
low (subregulatory) concentration by fed-batch culture.

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Evolutionary Perspectives on the Role of Plant Secondary

Metabolites
R. Delgoda, J.E. Murray, in Pharmacognosy, 2017

7.1 What are Secondary Metabolites?

A substantial portion of the human daily diet is formed of plants and plant constituents and
their nutritional values have been extensively studied. These nutritional components of
carbohydrates, lipids and amino acids are produced biosynthetically by photosynthetic green
plants which form the root of almost all food chains on earth, and are known as primary
metabolites.
In addition to the essential primary metabolites, plants are estimated to be able to
biosynthesize at least a million [1] other diverse compounds as well, with related plant
families and species expressing combinations of similar compounds. Selective expression of
these compounds has in fact helped scientists classify plants into different chemotaxonomic
groups. These compounds, typically of low molecular weight, appear not to contribute
directly to the primary functions of the plant, and are therefore known as “secondary
metabolites.” The concept of secondary metabolites can be attributed to Kossel [2] who
distinguished them from primary metabolites.
Although secondary metabolites were considered as waste products in the past, growing
evidence has emerged displaying an intricate role in providing a distinct evolutionary
advantage to the plants that express them, either directly or through indirect connections
with others. Thus the definition of what a secondary metabolite is has changed somewhat
over the years. The most accepted definition of secondary metabolites consider them to be
naturally produced substances that do not play an explicit role in the internal economy of the
organism that produces it [3,4] and stands in direct contrast to primary metabolites, which
maintain fundamental cellular life processes. These secondary metabolites are argued to play
an important role in the survival of the species that produces them via critical interactions
with its environment.

Secondary metabolites are low molecular weight compounds that have no recognized role
in the maintenance of fundamental life processes in the plants that synthesize them, but
have an important role in the interaction of the plant with its environment [5].

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BIOCHEMICAL AND MODERN IDENTIFICATION TECHNIQUES |

Food Spoilage Flora (Yeasts and Moulds)
George G. Khachatourians, Dilip K. Arora, in Encyclopedia of Food Microbiology, 1999

Fungal Volatile and Secondary Metabolites

Secondary metabolites are outward-directed differentiation products of normal cellular
metabolism that may function as chemical signals between organisms or species. Different
analytical methods can be applied for the separation and detection of secondary metabolites.
Some of these methods involve the use of thin layer chromatography, gas chromatography,
high performance liquid chromatography (HPLC), micellar capillary electrophoresis, flow
injection electrospray mass spectrometry, ultraviolet diode array detection and nuclear
magnetic resonance detection. There are different opinions on the use of secondary
metabolites in characterization and identification of filamentous fungi. Some workers believe
that secondary metabolites are strain-specific, whereas others think that they are very
sensitive to growth and environmental factors, and therefore could not be considered for
diagnostic purposes. However, in some of the few genera of filamentous fungi, secondary
metabolites have been shown to be very reliable and act as highly diagnostic characters. For
example, secondary metabolites have been particularly effective in identifying some of the
most common food-spoilage fungi such as species of Penicillium, Aspergillus and Fusarium.
The food-borne terverticilliate penicillia are very difficult to characterize by using traditional
characters, but the secondary metabolites of many of these species have given a very clear
identification system of this most complex species group. Several closely related species of
Penicillium can be separated using secondary metabolites by using diode array detection or
flow injection analysis electrospray mass spectrometry. There are several pitfalls in using
secondary metabolites for identification of food-borne fungi. (1) Based on characterization of
these metabolites, only highly specialized taxonomists are able to make a correct
identification. (2) No simplified diagnostic procedure has been developed for fungi which
commonly contaminate foods. (3) Most fungal species have the ability to produce secondary
metabolites, but in some cases a particular taxon or isolate needs specific stimuli to initiate
the accumulation of some of these metabolites. (4) Several types of secondary metabolites
may remain unnoticed because of inefficient extraction procedures or low analytical
sensitivity or low reproducibility under different growth and metabolic conditions.
Fungi often develop characteristic odours due to the production of unique combinations of
volatile metabolites like alcohols, ketones, esters, terpenes and other hydrocarbons. However,
volatile metabolites have only rarely been used for identification purposes. Recent studies
have shown that toxic and non-toxic isolates of both Aspergillus and Fusarium species can be
distinguished from each other based on their production of sesquiterpenes. Similarly, it has
been demonstrated that a large number of Penicillium species can also be classified based on
profiles of volatile metabolites. Based on volatile profiles, Penicillium roqueforti and P.
commune can be easily identified; the latter species is most frequently a contaminant of
cheese.

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Animal Metabolites
K.-D. James, in Pharmacognosy, 2017

19.1.2.2 Secondary Metabolites

Secondary metabolites that can be created from primary ones are not directly involved in the
normal growth, development, and reproduction of the organism. They are molecules which
are primarily involved in the overall maintenance/homeostasis of the organism. Secondary
metabolites specifically modulate health-maintaining processes, including excretion of waste
and toxic products from the body. That means, sustaining the overall health and functional
status of the cells within organ systems of the body, the principal function of secondary
metabolites. As an illustration, one could cite the biotransformation of tryptophan, a primary
metabolite, into Actinomycin, which is a secondary metabolite [8].
Though the production of metabolites is a natural chemical and bioenzymatic reaction that
occurs during metabolism in the body of all organisms, metabolites may also be produced as
by-products of the body’s reaction to exogenous/external substances or stimuli, such as
medications and/or antigens [9]. The network of metabolites, working with enzyme reactions
during the entire process of metabolism, is called the metabolome [10]. The metabolome
involves/implicates all the series of combinations of cascading reactions between enzymes
and substrates in the steps of metabolism, and ending in the production of the primary and
secondary metabolites.

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Application of Plant Biotechnology

Saurabh Bhatia, in Modern Applications of Plant Biotechnology in Pharmaceutical Sciences, 2015

5.3.1.1 Production of Secondary Metabolite

Plant secondary metabolites are the most valuable phytochemicals of plant secondary
metabolism and possess sufficient chemical or structural complexity so that artificial
synthesis is difficult or not currently possible. Various culturing techniques used for the
production of secondary metabolites are mentioned in Table 5.2. Occurrence, availability, and
structural diversity of these active principals vary according to environmental conditions.
Yield of these therapeutic compounds from different plant sources has been a major concern
over last few decades. In addition factors that regulate or affect their metabolism require a
basic in vitro model where plant sample can be experimented on to increase the yield of
these active principals. Plant cell culture holds much promise as a method for producing
complex secondary metabolites in vitro. A breakthrough in cell culture methodology occurred
with the successful establishment of cell lines capable of producing high yields of secondary
compounds in cell suspension cultures [27]. In plant cell biotechnology, metabolic
engineering is an emerging branch that plays a vital role in triggering specific pathways for
the production of secondary metabolites (metabolomics). For the production of specific
secondary metabolite, activation of a specific path way is necessary. This may occur when
transcription triggers the expression of a specific gene to participate in production of those
proteins that are further taking part in biosynthetic pathways as activator molecules for
triggering specific secondary metabolites. This whole process requires a combined
knowledge of transcriptonomics, genomics, proteomics, and metabolomics. Metabolic
engineering is a branch to engineer/optimize parameters involved in the high production of
secondary metabolites by using various tools such as proteomics, genomics,
transcriptonomics, and metabolomics. The primary purpose involved here is to produce high-
quality secondary metabolites with improved yield. Metabolic engineering also creates a
good understanding of biosynthetic pathways and their respective end products. Various
reports on secondary metabolite production through in vitro techniques are mentioned in
Table 5.3.

Table 5.2. Strategies for Improving the Yield of Secondary Metabolites

Sr. No. Strategies for improving the yield of secondary metabolites

1. Culture conditions and their optimization

2. Media optimization

3. Optimization of sterilization protocol

4. Hormonal supplementation and its optimization

5. Elicitation

6. Precursor feeding

7. Immobilization and permeabilization

8. Metabolic engineering: alteration of metabolic pathways (metabolomics)

9. Dependent on type of explants (elite variety) and type of culture (organ, cell, callus, embryo, etc.)

10. Identification of genes and expression of encoding key enzymes for secondary metabolite synthesis

11. Genetic manipulation

12. Scale-up technique: bioreactors (engineering considerations and their optimization)

13. Role of endophytes

14. Role of differentiation (cytodifferentiation and cellular organization)

15. Type of culturing technique

16. Hairy root culture

17. Nature of explants

18. Biotransformation

19. Use of mutagen

Table 5.3. Some Reported Secondary Metabolites Produced by Plant Tissue Culture

Secondary Culture

metabolite Plant species Culture condition type Biological action Reference

L-Ephedrine Ephedra sp. MS + kinetin + 2,4- S Sympathomimetic [28]

Amarogentin Swertia japonica MS + IAA HR Bitter tonic and [29]

hepatoprotective

Anthocyanin Vitis vinifera MS + BAP + NAA S Protects against myriad of [30]

human diseases

Anthraquinones Cassia acutifolia MS + 2,4-D + S Purgative [31]

kinetin

Artemisinin Artemisia spp. MS + IAA + kinetin HR Antimalarial [32]

Asiaticoside Centella asiatica MS + 2,4-D HR Wound healing [33]

Azadirachtin Azadirachta indica MS + 2,4-D S Insecticidal [34]

Berberine Coscinium MS + IAA + BAP C Antibacterial, anti-inflammatory [35]

fenestratum

Betacyanin Phytolacca MS + 2,4-D S Antioxidant [36]

americana

Caffeine Coffea arabica MS + 2,4-D + C CNS stimulant [37]

kinetin

Camptothecin Ophiorrhiza MS + BA + kinetin Sc Anticancer [38]

rugosa

Capsaicin Capsicum annuum MS + 2,4-D + S Cures rheumatic pain [39]

kinetin

Cardenolides Digitalis purpurea MS + BA S Cardioactive property [40]

Catechin Rheum ribes MS + IBA + BA C Antioxidant [41]

Catharanthine Catharanthus MS + 2,4-D + UV-B S Nicotinic receptor inhibitor, [42]

roseus radiation anticancer property

Cathin Brucea javanica MS + IAA + GA3 S Psychoactive drug [43]

Codeine Papaver spp. LS + BA + NAA Analgesic [44]

Cryptosin Cryptolepis B5 + 2,4-D + C Cardioactive property [45]

buchanani kinetin

Diosgenin Dioscorea MS + 2,4-D S Synthesis of medicinal steroids [46]

deltoidea

Eleutherosides Eleutherococcus MS + 2,4-D S Antidiabetic effects [47]

senticosus

Forskolin Coleus forskohlii MS + IAA + kinetin HR Anticancer, glaucoma [48]

Glycyrrhizin Glycyrrhiza glabra MS + 2,4-D + GA3 HR Expectorant and treatment of [49]

peptic ulcer

Gymnemic acid Gymnema MS + 2,4-D + IAA C Antidiabetic [50]

sylvestre

Hyoscyamine Datura MS + IAA HR Anticholinergic, antispasmodic [51]

stramonium

Hypericins Hypericum MS + BA + IAA ML Antidepressant [52]

perforatum

Indole alkaloid C. roseus MS + 2,4-D + GA3 S Anticancer [53]

vanadium

Isoflavones Psoralea MS + TDZ + BAP ML Antioxidant [54]

corylifolia

Lignan Linum flavum MS + IAA + GA3 HR Anti-inflammatory [55]

and antioxidant effects

Lupeol, Rutin Hemidesmus MS + BAP + NAA Sc Antioxidant [56]

indicus

Plumbagin Plumbago rosea MS + CaCl2 C Antimicrobial, anti- [57]

inflammatory

Quercetin Pluchea lanceolata MS + NAA + BAP C Antioxidant [58]

Quinine Cinchona MS + kinetin S Antimalarial [59]

ledgeriana

Reserpine Rauvolfia MS + IAA + Cu2 + C Hypotensive [60]

serpentina

Resveratrol Vitis vinifera MS + IAA + GA3 + C Cardiac and anticancer effects [61]

UV

Rutin Fagopyrum MS + NAA HR Antioxidant Treatment of [62]

esculentum capillary bleeding

Shikonin Lithospermum MS + 2,4-D + HR Anti-HIV therapeutic agents [63]

erythrorhizon kinetin

Silymarin Silybum MS + IAA + GA3 HR Hepatoprotective [64]

marianum

Umbelliferone Ammi majus MS + BAP SL Sunscreen agent [65]

Valepotriates Centranthus ruber MS + IAA + kinetin HR Putative anxiolytic effect [66]

Vincristine Catharanthus MS + 2,4-D + GA3 S Anticarcinogenic [67]

roseus

Withanolide A Withania MS + IAA + kinetin HR Sedative and antirheumatic [68]

somnifera

S: Suspension; HR: Hairy root; C: Callus; Sc: Shoot culture; SL: Shootlet; ML: Multiple shoots

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Fungal Metabolites
D.K. Daley, ... S. Badal, in Pharmacognosy, 2017

20.6 Applications of Secondary Metabolites

A number of secondary metabolites function as antibacterial, antifungal, or antitumor agents
[12,24]. In 1995, there were approximately 12,000 known antibiotics and of this amount
approximately 22% were produced by fungi [5,20]. In 2010, it was estimated that fungi
accounted for 61% of the microbial metabolites [25]. Included are the broad-spectrum
penicillins from Penicillium sp., and the cephalosporins form Cephalosporium sp. Griseofulvin
is a broadly used antifungal agent first isolated form Penicillium griseofulvin. It acts by
inhibiting fungal mitosis and thus fungal growth and is commonly used as a topical
antifungal agent [26]. Taxol, from the fungus Taxomyces andreanae, is an approved agent for
the treatment of breast and ovarian cancer [5,20]. Cyclosporin A (from Trichoderma
polysporum) was originally indicated as an antifungal agent but is now widely known for its
powerful immunosuppressive activity [27,28]. It is used to prevent rejection in patients who
have undergone organ transplant surgery.
Secondary metabolites may also function as hormones, e.g., the gibberellins from Gibberella
fujikuroi, used in the production of seedless grapes [18], to increase vegetable yield, increase
the rate of barley malting and improve malt quality, control flowering, seed germination, and
stem elongation, as well as to lower the time required for reaping lettuce and sugar beet seed
crops [29]. The estrogen zearelanone is also produced by Gibberella sp. (Gibberella zeae) and is
used to increase growth and feed efficiency in sheep and cattle [5,20]. Secondary metabolites
can have negative effects as is seen with the aflatoxins which cause a number of diseases.
These include both chronic and acute conditions, such as growth retardation, immune
suppression, cancer, and in severe cases, death [30,31].
Other industrial applications of fungal secondary metabolites include the use of pigments.
The carotenoid astaxanthin from the yeast Phaffia rhodozyma gives crustacean shells and the
flesh of salmonids their orange-pink color when boiled [5,20]. β-Carotene is also industrially
produced in Russia from the fungus Blakeslea trispora [32] and functions as a pigment in
plants such as carrots and also aids in photosynthesis and photoprotection. Polyunsatured
fatty acids that form an important part of heart health and lower the levels of “bad
cholesterol” can be accumulated through the use of fungal species like Morteriella isabellina
and Mucor circinelloides [32].
Secondary metabolites have applications in agriculture, medicine, pharmaceutical, and
manufacturing industries. Some metabolites, such as the ergot alkaloid, lysergic acid
diethylamide (LSD), have been abused due to their intoxicative effects. Despite this, fungal
secondary metabolites show great diversity and application in a number of industries where
they play key roles.

Lysergic acid diethyl amide, commonly known as LSD, is a member of the ergot alkaloids
and was accidentally discovered as a hallucinogen. Prior to its use as a recreational drug,
LSD was used in psychiatry to treat schizophrenia.

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Synthetic Biology and Metabolic Engineering in Plants and

Microbes Part A: Metabolism in Microbes
J.W.A. van Dijk, C.C.C. Wang, in Methods in Enzymology, 2016

Abstract
Heterologous expression of fungal secondary metabolite genes allows for the product
formation of otherwise silent secondary metabolite biosynthesis pathways. It also allows
facile expression of mutants or combinations of genes not found in nature. This capability
makes model fungi an ideal platform for synthetic biology. In this chapter a detailed
description is provided of how to heterologously express any fungal secondary metabolite
gene(s) in a well-developed host strain of Aspergillus nidulans. It covers all the necessary
steps from identifying a gene(s) of interest to culturing mutant strains to produce secondary
metabolites.

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