Feed-forward inhibition

Gordon, E. L., Pearson, J. D., and Slakey, L. L. (1986). The hydrolysis of extracellular adenine nucleotides by cultured endothelial cells from pig aorta. Feed-forward inhibition of adenosine... 

Figure 6.3.2 shows the feed-forward design, in which acrolein and water were included, since previous studies had indicated some inhibition of the catalytic rates by these two substances. Inert gas pressure was kept as a variable to check for pore diffusion limitations. Since no large diffusional limitation was shown, the inert gas pressure was dropped as an independent variable in the second study of feed-back design, and replaced by total pressure. For smaller difftisional effects later tests were recommended, due to the extreme urgency of this project. 

CUMULATIVE FEEDBACK INHIBITION FEEDBACK INHIBITION FEED-FORWARD ACTIVATION "FELIX,"... 

Pathways in the central nervous system. A shows two relay neurons and two types of inhibitory pathways, recurrent and feed-forward. The inhibitory neurons are shown in black. B shows the pathway responsible for presynaptic inhibition in which the axon of an inhibitory neuron synapses on the axon terminal of an excitatory fiber. C Diagram illustrating that dendrites may be both pre-and postsynaptic to each other, forming reciprocal synapses, two of which are shown between the same dendrite pair. In triads, an axon synapses on two dendrites, and one of these dendrites synapses on the second. In serial synapses, a dendrite may be postsynaptic to one dendrite and presynaptic to another, thus connecting a series of dendrites. Dendrites also interact through low-resistance electrotonic ("gap") junctions (two of which are shown). Except for one axon, all... 

Pyrimidine synthesis is controlled at the first committed step. ATP stimulates the aspartate transcarbamoylase reaction, while CTP inhibits it. CTP is a feedback inhibitor of the pathway, and ATP is a feed-forward activator. This regulation ensures that a balanced supply of purines and pyrimidines exists for RNA and synthesis. 

The flux through a metabolic pathway is invariably controlled or regulated, most commonly by Feedback Inhibition, but also through Feed-forward activation. Regulation is one of the things that makes biochemistry "biological" and it will be a focus in our study. 

Cellular cholesterol levels are regulated, not only by feedback inhibition of cholesterol synthesis, but also by feed-forward regulation of cholesterol metabolism. Excess cholesterol is metabolized to oxysterols. In addition to blocking SCAP-facilitated proteolysis of SREBP and thereby downregulating endogenous cholesterol synthesis and LDL receptor levels, oxysterols also activate bile acid synthesis (Chapter 15) and cholesterol esterification, which further reduces the cellular content of unesterified cholesterol. 

Other small molecules can act as feed-forward activators. For example, in DNA synthesis, the amounts of purine and pyrimidine nucleotides must be kept roughly equal. The enzyme aspartate tran-scarbamoylase is feedback-inhibited by CTP, the product of its metabolic pathway, and feed-forward-activated by ATP. If there is an excess of pyrimidines, inhibition by CTP slows the reaction, while if there is an excess of purines, ATP activates the enzyme, ultimately increasing the amount of pyrimidines in the cell. 

Stimulation of PK In liver, pyruvate kina.se is stimulated by fructose 1,6-bisphosphate (feed-forward stimulation). This is especially important during the transition from fasting (gluconeogenesis, PK inhibited) to hpogenesis (PK active) (Chapter 21). 

High intracellular concentrations of fructose 6-phosphate activate a second enzyme, phosphofructokinase-2, which catalyses the synthesis of fructose 2,6-bisphosphate from fructose 6-phosphate (Figure 10.4). Fructose 2,6-bisphosphate is an allosteric activator of phosphofructokinase and an allosteric inhibitor of fructose 1,6-bisphosphatase. It thus acts to both increase glycolysis and inhibit gluconeogenesis. This is feed-forward control — allosteric activation of phosphofructokinase because there is an increased concentration of substrate available. 

If alanine accumulates in muscle, it acts as an allosteric inhibitor of pyruvate kinase, so reducing the rate at which pyruvate is formed. This end-product inhibition of pyruvate kinase by alanine is over-ridden by high concentrations of fructose bisphosphate, which acts as a feed-forward activator of pyruvate kinase. ATP is an inhibitor of pyruvate kinase, and at high concentrations acts to inhibit the enzyme. More importantly, ATP acts as an allosteric inhibitor of phosphofructokinase (section 10.2.2.1). This means that, under conditions in which the supply of ATP (which can be regarded as the end-product of all energy-yielding metabolic pathways) is more than adequate to meet requirements, the metabolism of glucose is inhibited. 

In the feed forward stage the net input to each node is the sum of the weighted outputs of the nodes in the previous layer. The outputs of nodes in one layer are transmitted to nodes in another layers through links that amplify or attenuate or inhibit such outputs through weighting factors. Objectives of the stage are to obtain calculated outputs from the output layer and determine system errors between the calculated output and the desired output. 

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