90 the Tricarboxylic Acid Tca Cycle is a Continuous Loop of How Many Metabolic Reactions

Bacterial Metabolism–Coupled Energetics

R.S. Prakasham , B. Sudheer Kumar , in Microbial Electrochemical Technology, 2019

2.1.2.2.3 Reverse Tricarboxylic Acid Cycle

The reverse tricarboxylic acid cycle (rTCA) is also known as reverse Krebs cycle or the reverse citric acid cycle. In this cycle a sequence of metabolic pathways operate to produce carbon compounds (energy rich compounds) from carbon dioxide and water, and hence it is considered to be an alternative to photosynthesis or fixation of inorganic carbon in the reductive pentose phosphate cycle or reductive carboxylation [35]. In general, in TCA cycle, organism generates energy via the oxidation of acetate generated from either carbohydrate or protein or lipid using terminal electron accepter. In rTCA, the citric acid cycle pathway runs in opposite direction to synthesize carbon compounds of interest utilizing numerous ATP molecules. The enzymes, unique to reverse TCA, include pyruvate:ferredoxin (Fd) oxidoreductase (acetyl-CoA   +   CO₂  +   2Fd_red  +   2H⁺  ⇌   pyruvate   +   CoA   +   2Fd_ox), ATP citrate lyase (ACL, acetyl-CoA   +   oxaloacetate   +   ADP   +   P _i   ⇌   citrate   +   CoA   +   ATP), α-ketoglutarate:ferredoxin oxidoreductase (succinyl-CoA   +   CO₂  +   2Fd_red  +   2H⁺  ⇌   α-ketoglutarate   +   CoA   +   2Fd_ox), and fumarate reductase (succinate   +   acceptor   ⇌   fumarate   +   reduced acceptor). Among them, ATP citrate lyase is the key regulatory enzyme of this cycle. There are numerous anaerobic organisms that utilize a cyclic reverse TCA cycle, and the best example includes organisms Chlorobium thiosulfatophilum (classified under Thermoproteus) which are characterized as a hydrogen–sulfur autotroph [35]. Analysis of carbon flux of anoxygenic green sulfur bacterium, Chlorobaculum tepidum, revealed that rTCA cycle in this bacterium is active. Tang et al. [36] reported that the rTCA cycle is active during autotrophic and mixotrophic growth, whereas the flux from pyruvate to acetyl-CoA is very low; acetyl-CoA is synthesized through the rTCA cycle and acetate assimilation, whereas pyruvate is largely assimilated through the rTCA cycle; and acetate can be assimilated via both the RTCA and the oxidative TCA cycle. rTCA cycle mainly requires electron donors and often times, bacteria use inorganic compounds such as hydrogen, sulfide, or thiosulfate or minerals for this purpose [35,37]. It is considered that this rTCA is the main metabolic pathway during prebiotic early-earth conditions and hence is of great interest in the research of the origin of life. The differences between TCA and rTCA cycle is exemplified in Table 2.1.5.

Table 2.1.5. Metabolic Reactions of TCA and rTCA

Step	TCA Cycle	rTCA Cycle
1	Oxaloacetic acid   +   acetyl   ∼   CoA   –>   citric acid   +   HS   ∼   CoA	Oxaloacetic acid   +   NADH   +   H +–>   malate   +   NAD +
2	Citric acid—>   cis-aconitate   +   H2O	Malate   –>   fumarate   +   H 2 O
3	Cis-aconitate   +   H2O   –>   isocitrate	Fumarate   +   FADH 2–>   succinate   +   FAD
4	Isocitrate   +   NAD+  –>   oxalosuccinate   +   NADH   +   H+	Succinate   +   ATP   –>   succinyl   ∼   coA   +   ADP   +   Pi
5	Oxalosuccinate –>   α-ketoglutarate   +   CO2	Succinyl   ∼   coA   +   NADH   +   H+  –>   α-ketoglutarate   +   Acetyl   ∼   CoA   +   NAD+
6	α-Ketoglutarate   +   acetyl   ∼   CoA   +   NAD+  –>   succinyl   ∼   coA   +   NADH   +   H+	α-Ketoglutarate   +   NADH   +   H+  –>   isocitrate   +   NAD+  +   CO2
7	Succinyl   ∼   coA   +   GDP   +   Pi   –>   succinate   +   GTP	Isocitrate   –>   citrate
8	Succinate   +   FAD   –>   fumarate   +   FADH 2	Citrate   –>   oxaloacetic acid   +   acetyl   ∼   CoA +   ATP   +   Pi
9	Fumarate   +   H 2 O   –>   malate
10	Malate   +   NAD +   –>   oxaloacetic acid   +   NADH   +   H +

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Combined Gasification-Fermentation Process in Waste Biorefinery

Konstantinos Chandolias , ... Mohammad J. Taherzadeh , in Waste Biorefinery, 2018

3.4.2 The Reductive TCA Pathway

The reductive tricarboxylic acid (TCA) pathway is also known as Krebs, citric acid, and Arnon-Buchanan cycle. This pathway is less energy-consuming than the Calvin pathway and involves enzymes that are sensitive to O ₂. Therefore, it is present in both anaerobes and aerophiles that can grow at very low O₂ concentrations. The reverse TCA cycle is found in some Proteobacteria, green sulfur bacteria, microaerophilic bacteria of the phylum Aquificae, and archaea strains [75] (Table 5.6). This pathway was first discovered in the green sulfur bacterium Chlorobaculum thiosulfatiphilum [76].

Fig. 5.3 presents the main steps of the pathway. The key enzyme that converts citrate into acetyl-CoA and oxaloacetate is the ATP-citrate lyase. During a complete TCA cycle, two CO₂ molecules are fixed forming an acetyl-CoA and an oxaloacetate molecule [75]. Furthermore, the acetyl-CoA can be converted into pyruvate by another CO₂ molecule [77]. Moreover, a fourth CO₂ molecule can be assimilated by the pyruvate, which is consequently converted into oxaloacetate [76,77]. The α-oxoglutarate dehydrogenase and the citrate synthase reactions are normally irreversible. Enzymes such as ferredoxin, which are more powerful reductants than NADH, are required in order to promote the reactions in the opposite direction [69].

Fig. 5.3. The reductive TCA cycle [72].

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Stationary Phases in Gas Chromatography

In Journal of Chromatography Library, 1991

8.13 Fatty Acids and their Salts

Higher fatty acids and their alkali metal salts have been used as additives (10%) to low- or non-polar stationary phases (hydrocarbons, methylsilicones) in order to prevent tailing of hydrogen donor compounds (free carboxylic acids, alcohols, amino acid esters). It appears to be necessary for the carrier gas not to be completely dry [1002].

Trimer acid, a C₅₄ -tricarboxylic acid, which is only weakly polar, but has a relatively high McReynolds 5-constant and hence retains heterocyclics selectively has been directly applied as a stationary phase.

Heavy metal salts (Mn²⁺, Co²⁺, Ni²⁺, Cu²⁺, Zn²⁺) of the higher fatty acids are, in the molten state, superselective for the separation of amines and N-heterocyclics, owing to the strong coordination forces that act between these solutes and the metal atoms. These forces depend on steric factors. For example, α-, β- and γ-picolines and 2,6-lutidine could easily be separated [1003]. Whereas the McReynolds constants X, Z and U are below 100, Y is 231 and S as high as 544 (zinc-stearate) (see Table 75).

Table 75. McReynolds Constants of Fatty Acids and Zinc Stearate ^*)

Name	McReynolds constant
	X	Y	Z	U	S	H	I	K	L	M
SP 1200	067	170	103	203	166	166	145
Trimer acid	094	271	163	182	378	234	094	057	216	060
Zinc stearate	061	231	059	098	544	098	050	029	078	033

*)

After [324, 781, 783–784, 824]

Trimer acid
Structure: C54-tricarboxylic acid	Min. col. temp.: 20°C
	Max. col. temp.: 150°C
Stearic acid
Structure: CH3(CH2)16COOH	Max. col. temp.: 100°C
Behenic acid
Structure: CH3(CH2)20COOH	Max. col. temp.: 120°C
Zinc stearate
Structure: (C17H35COO)2Zn	Min. col. temp.: 50°C
	Max. col. temp.: 150°C
Copper stearate Structure: (C17H35COO)2Cu	Max. col. temp.: 160°C

Recommended Phase: Zinc stearate

Solvent: Chloroform, acetone

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Carbohydrates and Their Derivatives Including Tannins, Cellulose, and Related Lignings

Darla P. Henderson , Eric J. Toone , in Comprehensive Natural Products Chemistry, 1999

3.13.7.6 Oxalomalonate Lyase

Acetobacter suboxydans apparently lacks a functional tricarboxylic acid pathway and alternative amino acid biosynthesis pathways are required. ^404–408 In the 1960s, Cheldin and co-workers ^409,410 proposed a biosynthetic route to glutamate that relies on enzymatic reaction of glyoxylate and oxaloacetate to yield αhydroxy-γ-ketoglutarate. In 1966, this group reported the existence of such an aldolase (oxalomalonate lyase; EC 4.1.3.13; CAS 37290-63-4) in the vinegar producing Acetobacter. The enzyme exhibits a pH optimum near 6.0. αHydroxy-γ-ketoglutarate produced by enzymatic reaction was decarboxylated with hydrogen peroxide, yielding only d-malate, suggesting that the reaction is stereospecific. No reports of substrate specificity, retro-aldol reaction or mechanistic data are available in the literature to date.

Scheme 66.

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Fundamentals: Ligands, Complexes, Synthesis, Purification, and Structure

C. Pettinari , ... A. Drozdov , in Comprehensive Coordination Chemistry II, 2003

1.11.9 Polycarboxylic Acids

Several naturally occurring di- and tricarboxylic acids are involved in important biological processes as donor ligands—see, for example, L-tartaric and citric acid—and their chemical behavior has been the object of many studies. Chemists have realized that polycarboxylic ligands can function as chelating agents useful in several fields of application. For example, ethylenediamine-tetraacetic acid (EDTA) is commonly used as a chelating agent for a number of metal ions in analytical applications. In the last decades studies on polycarboxylate donors have increased enormously. Considerable effort has been devoted to the formation of metal–polycarboxylate assemblies. Polycarboxylate ligands function as connectors in coordination polymers that can offer new network architectures, many of which do not exist in natural solids. They find particular application in the crystal engineering of special geometrical and topological coordination polymers, potentially useful in catalysis, chemical absorption, metal-ion exchange and recognition, magnetism and electrical conductivity.

Polycarboxylic acids can basically be subdivided into three main classes: (i) donors containing only a carbon-based backbone; (ii) donors with carboxylate groups attached to a mono-, di-, or polyamine backbone; and (iii) donors built on aza-macrocycles, crown ethers, or calixarenes. The first class of ligands represents very useful building units for the design of highly porous and robust metal–organic frameworks. Porous solids usually find applications in the areas of ion exchange, separation, and catalysis. Research into the solid-state chemistry for the construction of extended solids from molecular building blocks attracts great interest, because of the advantages it offers for the design of materials. Cotton et al. have shown how it is possible to create discrete tetranuclear (pairs or loops), hexanuclear (triangles), octanuclear (squares), and dodecanuclear (cages) species, as well as 1-D, 2-D, or 3-D molecular nanotubes, by employing MM bonded dimetal entities as building units, instead of single metal ions, and equatorial and axial organic linkers represented by different polycarboxylato polyanions and neutral nitrogen-containing molecules, respectively. ²⁷¹

Classical dicarboxylate donors such as oxalate (171

), acetylene dicarboxylate (172), fumarate (173), propane-1,3-dicarboxylate (174), trans-1,4-cyclohexanedicarboxylate (175), phathalate (176), isophthalate (177), terephthalate (178), ferrocene-dicarboxylate (179), bicyclo[1.1.1]-pentane-1,3-dicarboxylate (180), trans-cyclopentane-1,2-dicarboxylate (181), and 1,4-cubanedicarboxylate (182) can be used as secondary building units as a basis for the design of highly porous and robust metal–organic carboxylate frameworks. ²⁷² These supramolecular arrays contain cross-section channel systems that occupy a volume constituting a large percentage of the structures, able to incorporate highly mobile guest molecules. ^273–275 The rigid-angular ligand 7-oxa-dibenzofluorene-3,11-dicarboxylate (183

) has been shown to be useful in the formation of a nanoscopic molecular rectangle for the construction of a 1-D coordination polymer by coordination with Cu^II and Co^II. ²⁷⁶ The 4,4′-diphenylcarboxylate (184) and 2,6-naphthalenedicarboxylate (185) can be employed in the coordination of Zn^II as infinite secondary building units in the formation of 3-D structures having a framework where catenation is forbidden. ²⁷⁸

The tri-functionalized 1,3,5-benzenetricarboxylate (trimesic acid) (186

) is one of the most widely employed triangular building units for the construction of 3-D porous networks characterized by high selectivity for guest binding in a tailored channel. The multidentate functionality of (186) imparts rigidity and stability to the resulting porous frameworks, even in the absence of guests, thus allowing examination of their inclusion chemistry. ^278–284 This donor can bind in several different modes, as depicted in Figure 11. ²⁸⁵

Figure 11.

Other examples of analogous, benzene-based, tricarboxylate donors are hemimellitic (187) and trimellitic acid (188), which show an enhanced lanthanide-sensitized luminescence, mainly with Tb^III. ²⁸⁶ The flexible, aliphatic-based trans-acotinic acid (189) reacts with [Co(η⁵-C₅H₅)₂]⁺[OH]⁻ generating a large, honeycomb-type structure, in which the resulting superanion [C₃H₃(CO₂H)₂CO₂ ⁻(H)^.C₃H₃(CO₂H)₂CO₂ ⁻] retains four –CO₂H groups available for "neutral" OOH···O hydrogen bonding, while the deprotonated CO₂ ⁻ forms a "charge-enhanced"-type hydrogen bond within the superanion. ²⁸⁷

Tetracarboxylate ligands such as 1,2,3,4-cyclobutanetetracarboxylate (190

), ²⁸⁷ 1,3,5,7-adamantanetetracarboxylate (191), ²⁸⁸ a bis-isophthalate derivative (192), ²⁸⁹ (2R,4R,6R,8R)-1,9-dihydroxy-3,5,7-trioxanonane-2,4,6,8-tetracarboxylate (193), ²⁹⁰ and 1,2,4,5-benzenetetracarboxylate (194) ²⁹¹ have been synthesized and applied as building blocks in open-metal-site porous materials. (190) forms supra-anionic organic frameworks held together by OOH···O and OOH···O⁻ hydrogen bonds which accommodate the diamagnetic [Co(η⁵-C₅H₅)₂]⁺ and the paramagnetic [Cr(η⁶-C₆H₆)₂]⁺ cations, respectively. ²⁸⁷ Ligand (192) has been used as a building block in the design of self-assembling, solid-state structures with cavities of defined size. The ordered porous materials are based on hydrogen interactions as intermolecular bonds (Figure 12). ²⁸⁹ Ligand (193) is an important lanthanide-sequestrant agent, able to bind also through ethereal oxygen atoms. ²⁹⁰

Figure 12.

Another wide class of polycarboxylate ligands is based on a mono-, di-, or polyamine backbone with three or more pendant carboxylate groups. These find potential applications in the field of radiometal-labeled agents, ²⁹² as therapeutic radiopharmaceuticals, ²⁹³ or as MRI contrasting agents used as diagnostic tools in medical bioassays. ²⁹⁴ The coordinating ability of ligands derived from ortho- (195

), meta- (196), or para-phenylenediamines (197), which can behave as dinucleating donors, is of special interest because of the intriguing magnetic properties of their transition-metal derivatives. ²⁹⁵

Several mono- and polyamino-carboxylate ligands have been synthesized, and their coordinating ability with respect to transition- and lanthanide-metal ions has been widely investigated. Van Eldik et al. have reported the systematic investigation of Fe^II polycarboxylate complexes with respect to their reactivity against nitric oxide and dioxygen in aqueous solution. ²⁹⁶ Their classification of polyamine-carboxylate ligands is very useful. Additional information about each of the following ligands reported here can be found in a series of very recent reviews. ^{292–295,297–301} Monoamino-dicarboxylates (Figure 13) are usually subdivided into three different subgroups. While in subgroup (a) the hydrogen can be exchanged by another noncoordinating group, in subgroup (b) it is exchanged by a further coordinating function, and in subgroup (c) by a heteroatom. Particular ligands based on hereocyclic rings are (198

) ³⁰¹ and (199), ²⁹⁶ whereas the ligand (200) ²⁹⁶ contains both amine and ethereal functions.

Figure 13.

Diamino-polycarboxylates are analogues of EDTA and can have a polymethylene chain of variable length as a spacer between the amine nitrogen atoms, in which branching, ethereal functionalities, or a fifth –COO group can also be present (Figure 14).

Figure 14.

Another big family of ligands is that derived by replacement of some or all four acetic acid end groups, without affecting the central ethylenediamine component (Figure 15).

Figure 15.

A large number of triamino-polycarboxylates also exist (Figure 16), with different coordinating or noncoordinating substituents bound to the central nitrogen atom.

Figure 16.

An additional series of triamino-polycarboxylates with substituents in the terminal COO end groups is shown in Figure 17.

Figure 17.

The polydentate donor (201

) contains six carboxylic acid groups and forms an anionic 1:1 complex with gadolinium, of formula [Gd(201)]³⁻. ³⁰¹

Other interesting donor ligands such as (202

) and (203), containing one or more pyridine rings, can react through their terminal –NCS or –NH₂ groups with amino acids and simultaneously chelate transition and lanthanide radio-metal ions. ²⁹⁷

A fullerene-based amine-carboxylate ligand (204

), able to form monolayer films with particular photoelectric conversion properties, has also been synthesized. ³⁰²

The third class of ligands we mention here is that of polyaza-macrocycles, crown ethers, and calixarenes bearing polycarboxylate arms. ^{293,294,299–301}

Several polyaza-macrocycle polycarboxylates with various cycle-size and COO⁻ units linked (Figure 18), useful as MRI contrast agents, have been synthesized. ²⁹⁴

Figure 18.

Polycarboxylate crown ethers such as (205

) are suitable ligands for potentiometric studies of mixed-metal complexes of Al³⁺ and alkali or alkaline-earth cations. ³⁰³ A similar (+)-18-crown-6-tetracarboxylic acid, chemically immobilized on a chiral stationary phase (CSP), can selectively recognize both enantiomers of some analytes. ³⁰⁴ Calixarene polycarboxylates such as (206) and (207) are useful ligands toward alkali- ^305,306 and also transition-metal ions, ^307,308 with applications in self-coextraction of sodium and in catalysis, respectively. A novel molecular-assembly mode has been shown by ferulic acid derivatives such as (208), which is a ligand able to give three kinds of noncovalent interaction, i.e., metal coordination, hydrogen coordination, and CH-π interaction, and to form stable dinuclear alkali-metal ions. ³⁰⁹

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Ammonia Metabolism and Hyperammonemic Disorders

Valerie Walker , in Advances in Clinical Chemistry, 2014

9.3.4 TCA cycle and the respiratory chain

One in vitro study reported increased glial TCA activity of rats with chronic liver failure [14], but others observed decreased activity in hyperammonemic disorders [125]. Increased ammonia inhibits the 2-oxoglutarate dehydrogenase complex [156], and possibly isocitrate dehydrogenase [30 review]. 2-Oxoglutarate is increased in brain of animals with acute liver failure or HA, and CSF levels in rats with chronic HE, although brain levels have been normal [10,153]. State III respiration is decreased in brain extracts from animals with acute HA, and activities of respiratory chain complexes I, II, and IV (cytochrome oxidase) are reduced in the cerebellum and cerebral cortex of rats with acute hepatic failure [153]. Complex IV expression and activity are reduced in the brain of spfmice [123]. Mitochondrial proliferation is observed in astrocytes of rats with chronic HE [153]. Exposure of astrocytes to a high concentration of ammonia (5   mmol/L) induces the mPT (mitochondrial permeability transition) with a sudden increase in mitochondrial permeability [153].

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System Metabolic Engineering Applications in Corynebacterium crenatum for l-Arginine Production

Zhiming Rao , ... Zhenghong Xu , in Current Developments in Biotechnology and Bioengineering, 2019

3.5.5 Carbon Flux Optimization of α-Ketoglutarate Metabolic Node

α-Ketoglutarate is a key intermediate in the TCA cycle and occupies the branch point of the TCA cycle and l-arginine biosynthesis (Fig. 14.3). Therefore, the carbon flux distribution at the α-ketoglutarate metabolic node has a great potential for optimization to enhance the l-arginine biosynthesis. Isocitrate dehydrogenase (ICD) encoded by icd oxidatively decarboxylates isocitrate to α-ketoglutarate and forms an NADPH (Fig. 14.3) [104]. To channel the isocitrate toward l-arginine synthesis, the ICD was overexpressed by implementation of an additional copy of icd in Cc4, resulting in strain Cc4-2icd. This strain showed higher l-arginine production and yield and faster glucose consumption rate, and the NADPH level was slightly increased [90].

In C. glutamicum, GDH encoded by gdh catalyzes the amination of α-ketoglutarate to l-glutamate. The extracellular glutamate production and intracellular glutamate concentration of C. glutamicum can be increased by overexpression of GDH [105]. To pull more α-ketoglutarate from TCA cycle into l-arginine biosynthesis, the GDH was overexpressed by implementation of an additional copy of gdh in Cc4-2icd, resulting in strain Cc4-2icd-2gdh. It seems likely that the overexpression of GDH had a negative effect on cell growth, and the l-arginine production increased slightly. More α-ketoglutarate was used to form glutamate, the TCA cycle flux downstream of α-ketoglutarate, and the formation of building blocks, redox power, or energy for cell growth were decreased, and these may result in the slowdown of cell growth. However, the l-arginine production per gram of biomass and l-arginine yield on glucose increased obviously.

The α-ketoglutarate dehydrogenase complex (ODHC) catalyzes the oxidative decarboxylation of α-ketoglutarate to succinyl coenzyme A (succinyl-CoA), and odhA gene encodes the E1o subunit of the ODHC [105]. Thus, to force more carbon flux toward l-arginine pathway, the ODHC activity needs to be attenuated. Similarly, attenuation of ODHC activity was carried out by optimization of odhA RBS. Thus, the RBSs designed by the RBS Calculator were used to replace the natural RBS of odhA in Cc4-2icd-2gdh, resulting in strains Cc5-200, Cc5-500, Cc5-800, and Cc5-1200. The results showed that it is effective to control the specific ODHC activity through the regulation of E1o subunit expression. Among these strains, the strain Cc5-800 showed the highest l-arginine production. Fed-batch fermentation of the Cc5-800 strain allowed production of 76.8   g/L l-arginine with a productivity of 1.12   g/L   h and yield of 0.372   g/g. Although the l-arginine productivity increased slightly, the l-arginine production per gram of biomass and l-arginine yield on glucose obviously increased [90]. Therefore, the overexpression of ICD and GDH and attenuation of ODHC activity could increase carbon flux into l-arginine pathway and decrease the carbon flux into anabolism and carbon loss by CO₂ release during oxidative decarboxylation of α-ketoglutarate.

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Biogeochemistry

J.W. Raich , ... D.J. Oliver , in Treatise on Geochemistry (Second Edition), 2014

10.16.2.1.2 Tricarboxylic acid cycle

Once within the mitochondria, malate and OAA are intermediates of the TCA cycle. Also within the mitochondria, malate can be converted to pyruvate by a plant-specific enzyme, malic enzyme. Pyruvate either formed within the mitochondria or imported from the cytosol is oxidized to acetyl-CoA and can be viewed as the substrate for the cycle. The cycle itself can in its simplest form be seen as a pathway that oxidizes that acetate to CO₂ with the extracted electrons given to the electron carriers NAD⁺ and FAD (Lambers et al., 2005; Nunes-Nesi and Fernie, 2007). Thus, the cycle completes the full oxidation of carbohydrates to CO₂ with a little of the resulting energy stored in the formation of a few ATP molecules but most of the potentially available energy stored in NADH or FADH₂. The combined reactions of glycolysis and the TCA cycle are

[10] $\text{Glucose}+4\text{ADP}+4\text{Pi}+8{\text{NAD}}^{+}+2\text{FAD}\to 6{\text{CO}}_2+4\text{ATP}+8\text{NADH}+2{\text{FADH}}_2$

This view of glycolysis and the TCA cycle, while appropriate for looking at the respiratory reactions of plants, is vastly oversimplified. These reactions lay within a broad metabolic network where intermediates are drawn off to provide the carbon backbone for a range of biosynthetic reactions and where, similarly, carbon extracted from several different pathways feeds into central carbon metabolism (Sweetlove et al., 2010).

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Application of 13C NMR Spectroscopy to Metabolic Studies on Animals

Basil Künnecke , in Carbon-13 NMR Spectroscopy of Biological Systems, 1995

5.3.4 Isotopomer Analysis and Modeling with Differential Equations

Chance et al. (1983) proposed a metabolic model of the TCA activity based on a set of simultaneous differential equations. For every reaction step involved in the modeled metabolism, differential equations describe the time-dependent concentration change of all possible isotopomers. The resulting system of interdependent equations is then solved for the rate constants of the different reaction steps. This approach requires the knowledge of the time course of label incorporation into strategic metabolites of the TCA cycle and their absolute concentrations. Clearly, the former requirement is met by serial measurements with ¹³C MRS, where pool sizes have to be determined by an alternative method. The accuracy of the calculation strongly depends on the achievable time resolution and SNR of the MR spectra. From a mathematical point of view, the enormous number of simultaneous differential equations resulting even from a simple model may impose further limitations and require judicious selection of data storage and computing algorithms.

Chance et al. (1983) successfully applied this method for the quantification of acetate and pyruvate metabolism in perfused rat hearts. Perchloric acid (PCA) extracts obtained from hearts perfused for designated times were analyzed with ¹³C MRS for the fractional enrichment in individual carbons of glutamate and aspartate, while standard biochemical assays provided metabolite concentrations. Metabolic modeling then allowed the calculation of the flux rates through the TCA cycle, transamination reactions and of the consumption of the substrates (see Section 5.6.).

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γ-Aminobutyric Acid (GABA): Biosynthesis, Role, Commercial Production, and Applications

Deo Rashmi , ... Altafhusain Nadaf , in Studies in Natural Products Chemistry, 2018

Catabolism of GABA

In general, GABA is mainly catabolized into succinate by GABA-T and SSADH which then moves to TCA cycle for further metabolism. In plants, SSA can be catabolized to succinate simultaneously with the production of NADH in mitochondria [221,222]. Alternately, γ-hydroxybutyrate (GHB) is produced by the action of SSA reductase activity [203,223,224]. SSADH activity is highly sensitive to the energy status in mitochondria [222]. Therefore, stressful conditions inhibit SSADH activity as NAD⁺/NADH ratio is low, SSA accumulates, and GABA-T is in turn inhibited in feedback manner [222,225]. It is in this case that SSA to GHB path is triggered and provides stress tolerance via detoxification of SSA [203,226]. In animals, GABA synthesis occurs only in neurons, whereas GABA catabolism occurs both in neurons and glia.

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