title: The Biochemistry of Haemonchus contortus and Other Parasitic Nematodes.
abstract: Different life cycle stages of Haemonchus contortus adapt to different ecosystems. This adaptation is accompanied by alterations in gene transcription and expression associated with the energy, amino acid, nitrogen, lipid and/or nucleic acid metabolism of the respective stages. For example, the aerobic metabolism of larvae depends on an efficient citric acid cycle, whereas the anaerobic metabolism of adults requires glycolysis, resulting in the production of volatile fatty acids, such as acetic acid and propionic acid. There are only few anthelmintics targeting nematode energy metabolism. In addition, H. contortus has reduced pathways for amino acid metabolism, polyamine metabolism and nitrogen excretion pathways. Moreover, nucleic acid metabolism comprising purine and pyrimidine salvage pathways as well as lipid metabolism are reduced. In addition, nematodes possess a particular composition of their cuticle. Energy production of adult worms is mainly linked to egg production and complex regulation of the neuromuscular system in both females and males. In this context, microtubules consisting of α- and β-tubulin heterodimers play a crucial role in the presynaptic vesicle transport. Due to the significant distinction of its quarternary structure in nematodes in comparison to other organisms, β-tubulin was identified as a major target for benzimidazoles used for anthelmintic treatment. Concerning the function of the neuromuscular system, acetylcholine, a ligand of the nicotinic acetylcholine receptor (nAChR), is the major excitatory neurotransmitter in H. contortus. In contrast, glutamate-gated chloride channels, calcium- and voltage-dependent potassium channels as well as γ-aminobutyric acid (GABA)A and its receptors act as inhibitory neurotransmitters and thus opponents to nAChR. For example, the calcium- and voltage-dependent potassium channel SLO-1 is an important target of emodepside, which is involved in the sensitive regulation of activatory and inhibitory receptors of the nervous system. Most of the modern anthelmintics target these different neuromuscular receptors. The mechanisms of resistance to anthelmintics, either specific or non-specific, are associated with changes in the molecular targets of the drugs, changes in metabolism of the drug (inactivation, removal or prevention of its activation) and/or increased efflux systems. The biochemical and molecular analyses of key developmental, metabolic and structural process of H. contortus still require substantial efforts. The nAChR, glutamate-gated chloride channel and calcium- and voltage-dependent potassium channel SLO-1 have long been known as being essential for nematode survival. Therefore, future research should be intensified to fully resolve the three-dimensional structures of these receptors, as has already been started for glutamate-gated chloride channel. With this knowledge, it should be possible to design new anthelmintics, which possess improved binding capacities to corresponding receptors.
authors.affiliation: WE Biology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. Electronic address: achim_harder@hotmail.de.
authors.forename: A
authors.initials: A
authors.lastname: Harder
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D055808:Drug Discovery; D004351:Drug Resistance; D004734:Energy Metabolism; D006188:Haemonchiasis / Q000469:parasitology*; D006189:Haemonchus / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008018:Life Cycle Stages; D050356:Lipid Metabolism; D009348:Nematoda / Q000187:drug effects / Q000502:physiology*; D009349:Nematode Infections / Q000469:parasitology*
chemical_list: D000871:Anthelmintics
keywords: Amino acid metabolism; Anthelmintic resistance; Biochemistry; Biochemistry of resistance; Energy metabolism; Environmental adaptation; Excitatory neurotransmitters; Haemochus contortus; Inhibitory neurotransmitters; Life cycle stages; Lipid metabolism; Nervous system; Nucleic acid metabolism