Pathways

Map kinases transduce responses to extracellular signals by a variety of routes, and communicate with other pathways through extensive crosstalk networks. A closely studied Map kinase cascade originates with tyrosine kinase activation, and activation of Ras. Ras activates Raf, Raf activates the Map kinase kinases Mek1 and Mek2 and these kinases activate downstream Map kinases like Erk1 and Erk2. Erk1 and Erk2 in turn activate transgenes like p35 through the Map kinase activated transcription factor EGR-1. Mek1 plays a central role in many different Map kinase pathways. Factors that activate Mek1 include growth factors like NGF, cytokines, chemokines, and phorbol ester, resulting in cellular proliferation and survival. Mek1 activation may also play a role in differentiation in neuronal tissues. In cultured neuronal PC-12 cells, NGF induces neurite outgrowth via Mek1 and the map kinase pathway. Constitutive activation of Mek1 can transform cells and may play a role in cancer.The crucial role of Mek1 in a variety of pathways including cellular transformation suggests that the cell must tightly regulate its activity. Cdk5 is a kinase that regulates the activity of Mek1. Although Cdk5 is a member of the cyclin-dependent kinase gene family, the activity of Cdk5 does not appear to be regulated by cyclins, but is activated by association with p35. Cdk5 does not act as a checkpoint kinase to regulate cell cycle progression, but acts as a regulatory kinase involved in other post-mitotic processes such as neuronal activity such as neuronal migration during development and neurite outgrowth. Mice lacking Cdk5 exhibit defects in neuronal development. One target of Cdk5 is Mek1. Phosphorylation of Mek1 by Cdk5 represses Mek1 activity and blocks downstream cellular responses. The activation of p35 by Map kinase pathways followed by deactivation of Map kinase signaling by the Cdk5/p35 complex completes the loop of a feedback circuit to terminate Map kinase signaling.

Photorespiration is a metabolic process that involves the oxygenation of D-ribulose-1,5-bisphosphate (RuBP) via the bifunctional enzyme rubisco (ribulose bisphosphate carboxylase/oxygenase). This reaction results in the production of one molecule of 3-phospho-D-glycerate and one molecule of 2-phosphoglycolate. The two substrates involved in this process are oxygen and carbon dioxide, which are competitive entities with the rubisco enzyme. This means that an increase in carbon dioxide inhibits the oxygenation of RuBP and vice-versa. The rate of oxygenation is also influenced by temperature, and is enhanced in high-temperature environments. This is due to the phenomenon that the solubility of carbon dioxide diminishes at a faster rate compared to oxygen, and that the specificity of the rubisco enzyme decreases with temperatures increasing between 5 and 35°C.

Photosynthesis involves the transfer and harvesting of energy from sunlight and the fixation of carbon dioxide into carbohydrates. This process occurs in higher plants, including Arabidopsis thaliana. Oxygenic photosynthesis requires water, which acts as an electron donor molecule. The reactions which involve the trapping of sunlight are known as "light reactions", and result in the production of NADPH, adenosine triphosphate, and molecular oxygen. The "dark reactions" are known as the Calvin cycle, and involve the use of the products of the light reactions to fix carbon dioxide and produce carbohydrates. Photosynthesis begins with photosystem II, located in the thylakoid membrane within chloroplasts, which captures light energy to transfer electrons from water to plastoquinone. This process generates oxygen as well as a proton gradient used to synthesize ATP. The D1/D2 (psbA/psbD) reaction center heterodimer binds P680, the primary electron donor of PSII as well as several subsequent electron acceptors. Next, the cytochrome b6-f complex mediates electron transfer between photosystem II (PSII) and photosystem I (PSI). Plastoquinol shuttles electrons from PSII to cytochrome b6-f complex. Plastocyanin shuttles electrons from cytochrome b6-f complex to PSI. Photosystem I is a plastocyanin-ferredoxin oxidoreductase which uses light energy to transfer an electron from the donor P700 chlorophyll pair to the electron acceptors A0, A1, FX, FA and FB in turn. The function of PSI is to produce the NADPH necessary for the reduction of CO2 in the Calvin-Benson cycle. Finally, the proton gradient allows ATPase to synthesize ATP from ADP. The light-independent Calvin-Benson cycle consist of nine reactions that take place in the chloroplast stroma. Beginning with the enzyme RuBisCO, D-ribulose-1,5-bisphosphate is converted into 3-phosphoglyceric acid. It requires magnesium ion as a cofactor. Next, chloroplastic glyceraldehyde 3-phosphate dehydrogenase catalyzes the conversion of glyceric acid 1,3-biphosphate into D-glyceraldehyde 3-phosphate. Then triose-phosphate isomerase catalyzes the conversion of D-glyceraldehyde 3-phosphate into dihydroxyacetone phosphate. Next, the enzyme fructose-bisphosphate aldolase catalyzes the conversion of dihydroxyacetone phosphate into fructose 1,6-bisphosphate. Then fructose-1,6-bisphosphatase catalyzes the conversion of fructose 1,6-bisphosphate into fructose-6-phosphate. It requires magnesium ion as a cofactor. Next, transketolase catalyzes the conversion of fructose-6-phosphate into xylulose 5-phosphate. It requires a divalent metal cation and thiamine diphosphate as cofactors. Then the enzyme ribulose-phosphate 3-epimerase is catalyzes the interconverson of xylulose 5-phosphate and D-ribulose 5-phosphate. Lastly, phosphoribulokinase catalyzes the conversion of D-ribulose 5-phosphate to regenerate D-ribulose-1,5-bisphosphate. An alternative pathway intersects the Calvin-Benson cycle providing another route to synthesize D-ribulose 5-phosphate and D-xylulose 5-phosphate, which both feed back into the main cycle, from dihydroxyacetone phosphate. This subpathway begins with the predicted enzyme sedoheptulose-1,7-bisphosphate aldolase theorized to catalyze the converson of glycerone phosphate and D-erythrose 4-phosphate into sedoheptulose-1,7-bisphosphate. Next, sedoheptulose-1,7-bisphosphatase catalyzes the conversion of sedoheptulose-1,7-bisphosphate into D-sedoheptulose 7-phosphate. Next, transketolase catalyzes the converson of D-sedoheptulose 7-phosphate into D-ribose 5-phosphate and D-xylulose 5-phosphate (which feeds back into the main cycle). Lastly, ribose-5-phosphate isomerase is the probable enzyme that catalyzes the interconverson of D-ribose 5-phosphate and D-ribulose 5-phosphate. D-ribulose 5-phosphate feeds back into the main cycle.

Photosynthesis involves the transfer and harvesting of energy from sunlight and the fixation of carbon dioxide into carbohydrates. This process occurs in higher plants, including Arabidopsis thaliana. Oxygenic photosynthesis requires water, which acts as an electron donor molecule. The reactions which involve the trapping of sunlight are known as "light reactions", and result in the production of NADPH, adenosine triphosphate, and molecular oxygen. The "dark reactions" are known as the Calvin cycle, and involve the use of the products of the light reactions to fix carbon dioxide and produce carbohydrates. The light-dependent reactions of photosynthesis begins with photosystem II, located in the thylakoid membrane within chloroplasts, which captures light energy to transfer electrons from water to plastoquinone. This process generates oxygen as well as a proton gradient used to synthesize ATP. The D1/D2 (psbA/psbD) reaction center heterodimer binds P680, the primary electron donor of PSII as well as several subsequent electron acceptors. Next, the cytochrome b6-f complex mediates electron transfer between photosystem II (PSII) and photosystem I (PSI). Plastoquinol shuttles electrons from PSII to cytochrome b6-f complex. Plastocyanin shuttles electrons from cytochrome b6-f complex to PSI. Photosystem I is a plastocyanin-ferredoxin oxidoreductase which uses light energy to transfer an electron from the donor P700 chlorophyll pair to the electron acceptors A0, A1, FX, FA and FB in turn. The function of PSI is to produce the NADPH necessary for the reduction of CO2 in the Calvin-Benson cycle. Finally, the proton gradient allows ATPase to synthesize ATP from ADP.

Phylloquinol biosynthesis is a pathway that occurs in the cytoplast by which geranylgeranyl diphosphate and 2-carboxy-1,4-naphthoquinol becomes phylloquinol, a naphtoquinone designated as vitamin K1 (along with phylloquinone) which posttranslatonally modifies precursors for blood coagualation. The three reactions of the subpathway to synthesize phytyl diphosphate from geranylgeranyl diphosphate are catalyzed by the same enzyme, geranylgeranyl dehydrogenase. This enzyme converts geranylgeranyl diphosphate into dihydrogeranylgeranyl diphosphate, dihydrogeranylgeranyl diphosphate into tetrahydrogeranylgeranyl diphosphate, and tetrahydrogeranylgeranyl diphosphate into phytyl diphosphate. The single reaction of the subpathway to synthesize 2-carboxy-1,4-naphthoquinone from 2-carboxy-1,4-naphthoquinol is catalyzed by 2-carboxy-1,4-naphthoquinol reductase. Next, the chloroplast-membrane-associated enzyme 2-carboxy-1,4-naphthoquinone phytyltransferase (coloured dark green in the image) converts phytyl diphosphate and 2-carboxy-1,4-naphthoquinone into demethylphylloquinone. Then, demethylphylloquinone dehydrogenase uses FAD as a cofactor to convert demethylphylloquinone into demethylphylloquinol. Lastly, demethylphylloquinol methyltransferase converts demethylphylloquinol into phylloquinol.

Physostigmine is a cholinesterase inhibitor used to treat glaucoma and anticholinergic toxicity. It is rapidly absorbed through membranes. It can be applied topically to the conjunctiva. It also can cross the blood-brain barrier and is used when central nervous system effects are desired, as in the treatment of severe anticholinergic toxicity. In the neuron, acetylcholine is synthesized form acetyl-coa and choline, and stored into synaptic vesicles. When an action potential arrives at the nerve terminal, voltage gated calcium channels open leading to an influx of calcium ions into the neuron. This triggers the docking of the synaptic vesicle and release of acetylcholine into the synapse. Acetylcholine acts on M3 receptors on the post synaptic membrane. M3 receptors are coupled to Gq signaling cascade. The downstream signaling causes the ciliary muscle of the eye to contract. This increase results in increased aqueous humor flow and a decrease in intraocular pressure. The acetylcholine in the synapse is cleared rapidly by acetylcholinesterase which breaks acetylcholine down into choline and acetate. Choline is taken back up into the presynaptic neuron and recycled to produce more acetylcholine. Physostigmine inhibits the acetylcholinesterase enzyme, which normally breaks down acetylcholine. The main pharmacological actions of this drug are believed to occur as the result of this enzyme inhibition, enhancing cholinergic transmission. Common adverse effects include nausea/vomiting, diarrhea, abdominal cramps, lacrimation, dyspnea, miosis, sweating.