User:Manasa Dileep

Arc Regulon
The Arc system or the Aerobic respiration control system is involved in the repression of aerobic functions under anaerobic conditions.It is a two component signal transduction system usually referred to as ArcAB and is composed of ArcA and ArcB. ArcA is a cytosolic response regulator with DNA binding domain and ArcB is a Histidine Kinase and membrane bound sensor kinase.

Arc A under microoxic conditions downregulates genes of the citric acid cycle, genes encoding a few important dehydrogenases like succinate dehydrogenase and glyoxylate cycle enzyme genes, and activates the cydAB gene which codes for cytochrome d oxidase, thereby shutting off the succinate dehydrogenase–cytochrome oxidase pathway and activating electron transport through the d-cytochrome, which has a higher affinity for oxygen.Signals from the electron transport chain in the membrane activate ArcB, which transmits the signal to ArcA and initiates the transcriptional regulation of the various genes.

ArcAB system down regulates the aerobic metabolism genes which leads to a diminished need for respiration during growth arrest and the repression of the ArcA regulon leads to minimization of the formation of reactive oxygen species and lessens oxidative ageing of essential proteins and is an important survival strategy.

The Arc regulon has been characterized in E.Coli and a few other facultative bacteria (many pathogens as well) and significant homologies can be found in humans and mammals in general.

Activation
ArcB does not sense oxygen content directly but instead, it senses the redox state through the oxidized form of the quinone electron carriers in the Ubiquinone-ubiquinol pool in the electron transport chain. ArcB is also modulated by the redox state of the Menaquinone pool and hence the MK/MKH2 ratio is also a determinant of the ArcB activity. Menaquinols would be the dominant activators under anoxic conditions, where the size of the Ubiquinone-ubiquinol pool is approximately one fifth the size of the MK-MKH2 pool.

Under anaerobic and microoxic conditions the MK-MKH2 pool predominates. Hence during microoxic conditions (low levels of oxygen between 0-20%) MKH2 predominates leading to activation of the ArcB kinase and in presence of low levels of oxygen (~20%) MKH2 is oxidized and ArcB gets inactivated due to the increased levels of MKs. Under slightly higher levels of oxygen (20-80%), the UQ-UQH2 pool predominates and UQH2 concentration is high leading to the activation of ArcB kinase. In fully aerobic conditions (80-100%),the UQH2 pool is oxidized, leading to increased levels of UQs resulting in the inactivation of the ArcB kinase activity. The UQs and MKs lead to the oxidation of the key cysteinses and thereby inactivate ArcB. This combined regulation of the ArcB sensor by the redox states of both the UQ pool and the MK pool is the complex mechanism by which ArcB undergoes auto-phosphorylation at different oxygen levels, and the activated kinase transfers the phosphate group to ArcA through the His→Asp→His→Asp phosphorelay. As shown in Fig2. Consequently,the phosphorylated ArcA regulates the genes transcriptionaly.



Hence ArcAB controlled gene expression occurs predominantly under conditions of scarce oxygen supply, rather than under fully anaerobic or aerobic conditions.

ArcA is regulated by Fnr in anaerobic conditions. The presence of Fnr activates the ArcA transcription and increases it by three to four times. Fnr binds to the arcA upstream regulatory region containing the promoter sequences.

Phosphorelay Mechanism
ArcB protein has three cytoplasmic domains: a primary transmitter domain (H1), a receiver domain (D1) and a secondary transmitter domain (H2) containing a conserved His292, Asp576, and a His717 respectively. As shown in Fig2.

After activation the H1 of ArcB is auto-phosphorylated at His292 using ATP. The phosphoryl group is then sequentially transferred to Asp576 of D1 and to His717 of H2 and from there to Asp54 of ArcA. The transfer of the phosphoryl group from His717 to ArcA is the crucial step, and this transfer is regulated by the redox conditions of the cell. However, the phosphoryl group on His292 could also be directly transferred to ArcA at a very low rate.

Repression by ArcA
After phosphorylation, ArcA gets activated and it represses the transcription of the cyoABCDE operon, which encodes cytochrome bo oxidase which has a high Vmax and low oxygen affinity (suited for aerobic respiration) and activates cydAB encoding cytochrome bd oxidase which has a low Vmax and high oxygen affinity (suited for microoxic respiration). Gene regulation under varied oxygen levels is achieved through the combined action of the oxygen sensing transcription factor Fnr and the ArcAB 2-component system. As shown in Fig1.

Phosphorylated ArcA regulates the expression of approximately 135 genes out of these genes its most important function is the repression of the expression of genes encoding dehydrogenases (pyruvate dehydrogenase and succinate dehydrogenase) of the tricarboxylic acid cycle and enzymes of the glyoxylate shunt. ArcA has DNA binding domains and it binds to promoter regions of TCA genes and represses their transcription.

Eukaryotic Homologue
ArcAB which is involved in regulation of metabolism and environmental signaling in E.Coli shares homologous genes in the mammalian postynaptic proteome with a significant (p < 0.05 binomial test) conservation of homologs between E. coli and humans.

An additional 19 E. coli pathways are involved in the sensing of extracellular environment including 18 members of the two-component signal transduction systems and the chemotactic signal transduction system. Of the 46 E.coli genes involved in 19 pathways, the sensor kinase arcB (homologous to human pyruvate dehydrogenase kinase, PDK3) and part of the ArcAB two-component signal transduction system are homologous.This suggests that a proportion of prokaryotic signaling systems capable of transmitting signals from the external environment to gene expression are also found in the in human postsynaptic proteins.

Hence, there is conservation between prokaryote and mammalian synapses of signaling mechanisms from receptors to transcriptional responses, a process essential to learning and memory in vertebrates.