Metabolic pathways glycogen

Metabolic pathways interconnect glycogen, fat, and protein reserves to store and retrieve ATP and glucose. 

There are now thought to be several thousand different genetic diseases, about 10% of which have known biochemical lesions. As has already been seen with the thyroid diseases and diabetes, the phenotypic manifestation, hemophilia, for example, may have genetically, biochemically or clinically different causes. Some of the biochemically identified disturbances, such as those affecting glycogen or galactose, have been important in establishing metabolic pathways (see Chapter 4). 

There were also less concrete considerations. In the early 1950s glycogenolysis was still believed to be completely reversible. UTP dependency and the glycogen synthase reactions had not yet been discovered nor had phosphofructokinase been shown to act irreversibly. The mechanism of protein synthesis was still a mystery. Laboratories studying proteolysis had shown that the peptide bond could be resynthesized by peptidases, although under very restricted conditions. Reversibility seemed to be an accepted property of the major metabolic pathways. 

A positive AG for this reaction conld also be achieved by a marked decrease in the concentration of glucose 6-phosphate. Why is this not feasible Glucose 6-phosphate is an important metabolic intermediate and is involved in several metabolic pathways (e.g. glycogen synthesis, glycolysis, pentose phosphate pathway). Lowering its concentration by the two orders of magnitude, which would be necessary, would markedly decrease the rates at which these important pathways could proceed. 

Inherited absence or mutations in enzymes involved in critical metabolic pathways—eg, the urea cycle or glycogen metabolism—are referred to as inborn errors of metabolism. If not detected soon after birth, these conditions can lead to serious metabolic derangements in infants and even death. 

The membrane-associated Akt kinase is now a substrate for protein kinase PDKl that phosphorylates a specific Thr and Ser residue of Akt kinase. The double phosphorylation converts Akt kinase to the active form. It is assumed that the Akt kinase now dissociates from the membrane and phosphorylates cytosolic substrates such as glycogen synthase kinase, 6-phosphofructo-2-kinase and ribosomal protein S6 kinase, p70 . According to this mechanism, Akt kinase regulates central metabolic pathways of the cell. Furthermore, it has a promoting influence on cell division and an inhibitory influence on programmed cell death, apoptosis. A role in apoptosis is suggested by the observation that a component of the apoptotic program. Bad protein (see Chapter 15) has been identified as a substrate of Akt kinase. 

The current state of Ser/Thr phosphorylation of a protein is determined by the relative activity of Ser/Thr-specific protein kinase and protein phosphatase. It is therefore imderstandable that the cell has had to develop special mechanisms to balance the two activities with one another, and, when needed, to allow kinase or phosphatase activity to dominate. One of the best investigated examples of coordinated activity of protein kinases and protein phosphatases is the regulation of glycogen metabolism in skeletal muscle. Glycogen metabolism is an example of how two different signals, namely a cAMP signal and a Ca signal meet in one metabolic pathway and control the activity of one and the same enzyme. 

The flow of intermediates through metabolic pathways is controlled by 1bir mechanisms 1) the availability of substrates 2) allosteric activation and inhibition of enzymes 3) covalent modification of enzymes and 4) induction-repression of enzyme synthesis. This scheme may at first seem unnecessarily redundant however, each mechanism operates on a different timescale (Figure 24.1), and allows the body to adapt to a wde variety of physiologic situations. In the fed state, these regulatory mechanisms ensure that available nutrients are captured as glycogen, triacylglycerol, and protein. 

Feedback can also be positive. Since AMP is a product of the hydrolysis of ATP, its accumulation is a signal to activate key enzymes in metabolic pathways that generate ATP. For example, AMP causes allosteric activation of glycogen phosphorylase, which catalyzes the first step in the catabolism of glycogen. As is shown in Fig. 11-5, the allosteric site for AMP or IMP binding is more than 3 nm away from the active site. Only a... 

Figure 11-4 Cascades of phosphorylation and dephosphorylation reactions involved in the control of the metabolism of glycogen. Heavy arrows show pathways by which glucosyl emits of glycogen are converted into free glucose or enter the glycolytic pathway. Green arrows trace the corresponding biosynthetic pathways. Gray arrows (— ) trace the...

A phosphorylated enzyme may be either more or less active than its dephos-phorylated form. Thus phosphorylation /dephosphorylation may be used as a rapid, reversible switch to turn a metabolic pathway on or off according to the needs of the cell. For example, glycogen phosphorylase, an enzyme involved... 

To figure out the biological meaning of the crossover (Figure 2.9 (C-E)), we need to know why this occurs. In mammals the answer seems to be a simple conseqence of power obtainable from different metabolic pathways maximum ATP turnover rates supported by fat oxidation in mammals are only about two-thirds the maximum ATP turnover rates supportable by glycogen oxidation (figure 2.10). The reasons for... 

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