Gluconeogenesis mechanisms

Gluconeogenesis Is Regulated by Allosteric and Substrate-Level Control Mechanisms... 

Step 1 of Figure 29.13 Carboxylation Gluconeogenesis begins with the carboxyl-afion of pyruvate to yield oxaloacetate. The reaction is catalyzed by pyruvate carboxylase and requires ATP, bicarbonate ion, and the coenzyme biotin, which acts as a carrier to transport CO2 to the enzyme active site. The mechanism is analogous to that of step 3 in fatty-acid biosynthesis (Figure 29.6), in which acetyl CoA is carboxylated to yield malonyl CoA. 

Problem 29.13 Write a mechanism for step 6 of gluconeogenesis, the reduction of 3-phospho-glyceryl phosphate with NADH/H+ to yield glyceraldehyde 3-phosphate. 

Metformin restrains hepatic glucose production principally by suppression of gluconeogenesis. The mechanisms involve potentiation of insulin action and decreased hepatic extraction of certain gluconeogenic substrates such as lactate. In addition, metformin reduces the rate of hepatic glycogenolysis and decreases the activity of hepatic glucose-6-phosphatase. Insulin-stimulated glucose uptake and glycogenesis by skeletal muscle is increased by metformin mainly by increased... 

Mechanism for Gluconeogenesis. Since the glycolysis involves three energetically irreversible steps at the pyruvate kinase, phosphofructokinase, and hexokinase levels, the production of glucose from simple noncarbohydrate materials, for example, pyruvate or lactate, by a reversal of glycolysis ( from bottom upwards ) is impossible. Therefore, indirect reaction routes are to be sought for. 

Goldstein, R.S., Contardi, L.R., Pasino, D.A. and Hook, J.B. (1987). Mechanisms mediating cephaloridine inhibition of renal gluconeogenesis. Toxicol. Appl. Pharmacol. 87(2) 297-305. 

Figure F -6. Cortisol and Glucagon Stimulate Gluconeogenesis Through Enhancer Mechanisms...

Mechanism of Action Aglucose elevating agent that promotes hepatic glycogenoly-sis, gluconeogenesis. Stimulates production of cyclic adenosine monophosphate (cAMP), which results in increased plasma glucose concentration, smooth muscle relaxation, and an inotropic myocardial effect. Therapeutic Effect Increases plasma glucose level. 

Mechanism of Action A natural hormone derived from animal sources, usually beef or pork, fhat is involved in normal mefabolism, growfh, and development, especially the central nervous system (CNS) of infanfs. Possesses cafabolic and anabolic effecfs. Provides both levothyroxine and liothyronine hormones. Therapeutic Effect Increases basal metabolic rate, enhances gluconeogenesis, stimulates protein synthesis. 

Depletion of ATP is caused by many toxic compounds, and this will result in a variety of biochemical changes. Although there are many ways for toxic compounds to cause a depletion of ATP in the cell, interference with mitochondrial oxidative phosphorylation is perhaps the most common. Thus, compounds, such as 2,4-dinitrophenol, which uncouple the production of ATP from the electron transport chain, will cause such an effect, but will also cause inhibition of electron transport or depletion of NADH. Excessive use of ATP or sequestration are other mechanisms, the latter being more fully described in relation to ethionine toxicity in chapter 7. Also, DNA damage, which causes the activation of poly(ADP-ribose) polymerase (PARP), may lead to ATP depletion (see below). A lack of ATP in the cell means that active transport into, out of, and within the cell is compromised or halted, with the result that the concentration of ions such as Na+, K+, and Ca2+ in particular compartments will change. Also, various synthetic biochemical processes such as protein synthesis, gluconeogenesis, and lipid synthesis will tend to be decreased. At the tissue level, this may mean that hepatocytes do not produce bile efficiently and proximal tubules do not actively reabsorb essential amino acids and glucose. 

This pancreatic islet hormone (see p. 311) stimulates gluconeogenesis by three mechanisms. 

Uptake of Ca2+ into cells, or release of this ion from intracellular stores, is a major regulatory mechanism in many if not all cells (see Section E). Mn2+ activates phosphoenolpyruvate carboxykinase (Eq. 13-46) and maybe a regulator of gluconeogenesis.142 Iron controls the synthesis of ferritin and of transferrin receptors137 (Chapter 16). The specific metal ions present in many biological macromolecules are likely to participate in additional regulatory processes. 

The activation of liver FDPase by formation of mixed disulfides invites speculation as to the possible role of this mechanism in vivo, and particularly as to the metabolic conditions which might result in such activation. Thus it is not likely that CoA serves as a physiological regulator since fatty acid catabolism during gluconeogenesis would leave... 

Another common mechanism for modulating hormonal response involves two (or more) hormonal inputs with both positive and negative effects (see fig. 24.21). The hypothalamic peptides, somatostatin and GRF, have opposite effects on GH synthesis and secretion. Similarly, glucagon and insulin have opposite effects on gluconeogenesis in the liver (see the discussion earlier in this chapter), and some of the effects of ecdysone on gene expression in insects are blocked by juvenile hormone (a terpene derivative fig. 24.22). 

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