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7.4Basic Flow of Metabolism

Metabolism in cells consists of a number of enzymatic reactions that constitute several metabolic pathways. Some of the main pathways are common to many organisms, while others are unique to each (or each biotic group). The basic metabolism flow in cells consists of the following three stages (Fig. 7-3):

(1) Complex materials (which may or may not be high molecular compounds) that function in the living body, such as proteins, polysaccharides and complex lipids, are made of basic units (amino acids, monosaccharides and fatty acids, respectively), and are broken down into these units when degraded. During this process, each metabolic system works independently.
(2) In sugars and lipids, conversion is made between these units and simpler basic metabolites via intermediates.
(3) Basic metabolites are interconverted.

In terms of energy, degradation from complex materials to constitutional units (1) means that free energy change (G˚’) is negative, and therefore proceeds by simple hydrolysis. However, to synthesize complex materials, energy needs to be added to produce activators (aminoacyl tRNA, sugar nucleotides, acyl-CoA, etc., as shown in Fig. 7-3), and synthesis is performed using the activators. In metabolism, material conversion occurs in both directions in many cases. However, if ∆G˚’ of the reaction in one direction is negative, the reverse reaction needs to occur through a different reaction by a different enzyme, in which ∆G˚’ of the whole reaction is made negative by coupling the reverse reaction with reactions that have high negative values, such as ATP hydrolysis (―▶▶ in Fig. 7-3). In reactions with negativeG˚’, two metabolic pathways exist: one involves hydrolysis (―▷ in Fig. 7-3), and the other involves energy being obtained by coupling the reaction with the synthesis of ATP and NADH or other reactions (―▷▷ in Fig. 7-3). Such ATP synthesis is called substrate-level phosphorylation, and is differentiated from that by ATP synthase discussed in Chapter 8. In the metabolism of sugars and fatty acids, energy is derived during the process of their degradation to basic metabolites (2), and is used in the reverse synthetic reactions. If materials are simply reconstructed in this way, the overall amount of energy becomes insufficient. For cellular activities to be sustainable, therefore, it is necessary to obtain energy only by degrading parts of sugars and fatty acids. This is the reason why glycolysis and β-oxidization*2 are generally considered to belong to the energy production system. For heterotrophs such as humans and E. coli to survive, therefore, the inflow of materials positioned toward the top of Figure. 7-3 (i.e., those with high energy content) must occur.
However, these materials are not generated ex nihilo. Phototrophs perform carbon dioxide fixation using solar energy (see the Column on this page), supplying high-energy materials to entire earth ecosystems (see Chapter 8 regarding photosynthesis). Phototrophs are therefore known as primary producers*3. Chemosynthetic bacteria that use energy from sources deep underground inside the earth are also primary producers. In short, life on earth owes its existence to the large energy flow found in the universe.
Here, we briefly discuss nitrogen metabolism. Autotrophs and many bacteria can produce amino acids from ammonia, while animals produce ammonia by breaking it down into amino acids; humans further convert it to urea before discarding it to be recycled by bacteria (see the Column on this page). An overall picture of metabolic pathways (metabolic maps) has been estimated for many organisms for which genome sequencing is complete, and this can be referred to online (see the Column on this page).

Fig. 7-3. Schematic diagram of basic metabolic pathways

Glu: Glutamic acid , Asp: Aspartic acid , Ala: Alanine , FBP: Fructose 1,6-biphosphate , G3P: Glyceraldehyde 3-phosphate , OAA: Oxaloacetic acid , 2-OG: 2-oxoglutarate

*2
β-oxidation: A reaction in which fatty acids are oxidatively degraded, cutting off two-carbon units in succession to produce acetyl-CoA. This occurs mainly in peroxisomes and to a lesser extent in some mitochondria.

*3
Primary producers: The organisms that first obtain carbon sources in ecosystems. These are eaten by herbivores and organisms (predators), which are in turn eaten by carnivores

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How the Michaelis-Menten Equation is derived

The substrate concentration dependency of the initial reaction rate is considered using the simple enzymatic reaction mentioned above. When the total concentration of an enzyme is E0,

E0 = [E] + [ES]                  (1)

When a steady state is assumed, the concentration of ES (intermediate) remains unchanged:

d[ES] / dt = k1[S][E] - (k-1 + k2) [ES] = 0

This can be rewritten to:

[S][E] - Km[ES] = 0           (2)

[E] is removed from (1) and (2):

[ES] = E0[S] / ([S] + Km)    (3)

(3) is assigned to the equation of the reaction rate (V):

V = k2[ES] = k2E0 / (1 + Km / [S]) = Vmax / (1 + Km / [S])

where Vmax = k2E0. If E (the enzyme) and S (the substrate) are in rapid equilibrium, and k1, k-1 >> k2, Km can be considered as the dissociation constant of the enzyme and the substrate, K = k-1 / k1.

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Fixation Cycle of Carbon and Nitrogen

Synthesis of organic compounds from carbon dioxide and ammonia - inorganic compounds - is an important reaction that supplies carbon and nitrogen to whole organism. The former (Column Fig. 7-1A) is provided through photosynthesis, and the latter (Column Fig. 7-1B, C) by various organisms. These reactions involve a circulatory reaction cycle in which inorganic compounds and energy (e.g., ATP) are input and organic compounds are output.

Column Fig. 7-1. Fixation systems for carbon and nitrogen

A) is the carbon dioxide fixation cycle of photosynthesis, and B) is the assimilation pathway of ammonia in microorganisms and plants. Both function as new fixation systems for carbon and nitrogen.
C) is the urea cycle, which functions as a pathway that converts ammonia generated in the animal body to urea. In microorganisms and other organisms, however, it functions as a pathway for nitrogen fixation.
RuBP: ribulose 1,5-bisphosphate , PGA: 3-phosphoglycerate , Glu: glutamic acid , Gln: glutamine , 2-OG: 2-oxoglutarate , Arg: arginine

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Bioinformatics of Metabolic Pathways

Knowledge of the genome sequence for various organisms enables the estimation of their metabolic pathways. Although various information technologies are necessary to achieve this (such as the estimation of gene regions, estimation of the functions of putative proteins and establishment of a database of known proteins), significant advancement in both computer hardware and software in recent years has made these technologies readily available on the Internet. In Japan, KEEG (the Kyoto Encyclopedia of Genes and Genomes) is a useful resource, and can be found at http://www.genome.ad.jp/kegg/.

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