Reductive acetyl-CoA

Another model is based on the fact that the genetic code shows a number of regularities, some of which have already been mentioned above. It is suspected that codons beginning with C, A or U code for amino acids which were formed from a-ketoacids (or a-ketoglutarate, 1-KG), oxalacetate (OAA) and pyruvate. This new model, which is quite different from the previous models, assumes that a covalent complex formed from two nucleotides acted as a catalyst for chemical reactions such as the reductive amination of a-ketoacids, pyruvate and OAA. More recent analyses suggest that the rTCA cycle (see Sect. 7.3) could have served as a source of simple a-ketoacids, including glyoxylate, pyruvate, OAA and a-KG. a-Ketoacids could, however, also have been formed via a reductive acetyl-CoA reaction pathway. The bases of the two nucleotides specify the amino acid synthesized and were retained until the modern three-letter codes were established (Copley et al., 2005). 

Reductive acetyl-CoA pathway 4-5 3 NAD(P)H, 2-3 ferredoxin, 1 H2 (in methanogens) Acetyl-CoA synthase/ CO dehydrogenase, formate dehydrogenase, pyruvate synthase C02 Acetyl-CoA, pyruvate Acetyl-CoA synthase/CO dehydrogenase, enzymes reducing C02 to methyltetrahydropterin... 

The Reductive Acetyl-CoA Pathway (Wood-Ljungdahl Pathway)... 

The reductive acetyl-CoA pathway is unique in several aspects. For example, the pathway makes extensive use of coenzymes (tetrahydropterin, cobalamin) and of... 

Figure 3.3 Reductive acetyl-CoA pathway. CD, CO dehydrogenase/acetyl-CoA-synthase , pyruvate ferredoxin oxidoreductase.

Pathways of autotrophic CO2 fixation A Reductive citric acid cycle Reductive acetyl CoA pathway I Reductive hydroxypropionante pathway Cathin-Bonion cycle... 

If we compare the reductive acetyl CoA pathway with the Calvin cycle and the reductive TCA pathways, we see that it presents some differences it is a linear unidirectional pathway, through which two molecules of CO2 are reductively... 

Scheme 9.4 Carbon dioxide fixation via the reductive acetyl-CoA pathway. Adapted from...

Iron Sulfur Compounds. Many molecular compounds (18—20) are known in which iron is tetrahedraHy coordinated by a combination of thiolate and sulfide donors. Of the 10 or more stmcturaHy characterized classes of Fe—S compounds, the four shown in Figure 1 are known to occur in proteins. The mononuclear iron site REPLACE occurs in the one-iron bacterial electron-transfer protein mbredoxin. The [2Fe—2S] (10) and [4Fe—4S] (12) cubane stmctures are found in the 2-, 4-, and 8-iron ferredoxins, which are also electron-transfer proteins. The [3Fe—4S] voided cubane stmcture (11) has been found in some ferredoxins and in the inactive form of aconitase, the enzyme which catalyzes the stereospecific hydration—rehydration of citrate to isocitrate in the Krebs cycle. In addition, enzymes are known that contain either other types of iron sulfur clusters or iron sulfur clusters that include other metals. Examples include nitrogenase, which reduces N2 to NH at a MoFe Sg homocitrate cluster carbon monoxide dehydrogenase, which assembles acetyl-coenzyme A (acetyl-CoA) at a FeNiS site and hydrogenases, which catalyze the reversible reduction of protons to hydrogen gas. 

Whereas catabolism is fundamentally an oxidative process, anabolism is, by its contrasting nature, reductive. The biosynthesis of the complex constituents of the cell begins at the level of intermediates derived from the degradative pathways of catabolism or, less commonly, biosynthesis begins with oxidized substances available in the inanimate environment, such as carbon dioxide. When the hydrocarbon chains of fatty acids are assembled from acetyl-CoA units, activated hydrogens are needed to reduce the carbonyl (C=0) carbon of acetyl-CoA into a —CHg— at every other position along the chain. When glucose is... 

One of these alternate models, postulated by Gunter Wachtershanser, involves an archaic version of the TCA cycle running in the reverse (reductive) direction. Reversal of the TCA cycle results in assimilation of CO9 and fixation of carbon as shown. For each turn of the reversed cycle, two carbons are fixed in the formation of isocitrate and two more are fixed in the reductive transformation of acetyl-CoA to oxaloacetate. Thus, for every succinate that enters the reversed cycle, two succinates are returned, making the cycle highly antocatalytic. Because TCA cycle intermediates are involved in many biosynthetic pathways (see Section 20.13), a reversed TCA cycle would be a bountiful and broad source of metabolic substrates. 

CO oxidation reaction. The spectral changes in Cluster C are followed hy Cluster B reduction with a rate constant that is similar to the steady-state value. On the other hand, the rate of formation of the characteristic EPR signal for the CO adduct at Cluster A is much slower. Its rate constant matches that for acetyl-CoA synthesis, hut is several orders of magnitude slower than CO oxidation. Therefore, it was proposed that the following steps are involved in CO oxidation (1) CO hinds to Cluster C, (2) EPR spectral changes in Cluster C are accompanied hy oxidation of CO to CO2 hy Cluster C, (3) Cluster C reduces Cluster B, and (4) Cluster B couples to external electron acceptors (133). 

CO is the precursor of the carbonyl group of acetyl-CoA (discussed earlier). An identical EPR signal is observed when other precursors of the carbonyl group of acetyl-CoA are reacted with CODH/ACS for example, CO2 in the presence of reductant 145) and pyruvate 164). Incubation with acetyl-CoA itself also gives rise to this EPR signal 185). 

Tyrosine. Figure 30-12 diagrams the conversion of tyrosine to amphibolic intermediates. Since ascorbate is the reductant for conversion of y>-hydroxyphenylpyru-vate to homogentisate, scorbutic patients excrete incompletely oxidized products of tyrosine catabohsm. Subsequent catabohsm forms maleylacetoacetate, fu-marylacetoacetate, fumarate, acetoacetate, and ultimately acetyl-CoA>... 

The NADPH-dependent reductase is active with C4 to C6 D-(-)-3-hy-droxyacyl-CoAs, it has no activity with L-(+)-substrates, and the reduction of acetoacetyl-CoA yields only D-(-)-3-hydroxybutyryl-CoA. The NADH-de-pendent reductase can use the L-(+)-enantiomers of these compounds and, in addition, C7, C8, and C10 L-(+)-3-hydroxyacyl-CoAs as substrates. From aceto-acetyl-CoA the NADH-dependent reductase produces only L-(+)-3-hydro-xybutyryl-CoA, but in the reverse direction it is active with both substrates [15]. 

If nitrogen (in the form of ammonia) is growth limiting, the potential applications of acetyl-CoA and NAD(P)H are restricted. Liberated NAD(P)H cannot be consumed for reductive syntheses, for instance of amino acids, it remains available and starts to inhibit citrate synthase [45, 46]. To the extent that the TCA cycle is thereby inhibited, acetyl-CoA should become available for the 3-ketothiolase, and could flow into poly(3HB) (Fig. 1, Table 1). 

Ketone bodies are formed in the liver mitochondria by the condensation of three acetyl-CoA units. The mechanism of ketone body formation is one of those pathways that doesn t look like a very good way to do things. Two acetyl-CoAs are condensed to form acetoacetyl-CoA. We could have had an enzyme that just hydrolyzed the acetoacetyl-CoA directly to acetoacetate, but no, it s got to be done in a more complicated fashion. The acetoacetyl-CoA is condensed with another acetyl-CoA to give hydroxymethylglutaryl-CoA (HMG-CoA). This is then split by HMG-CoA lyase to acetyl-CoA and acetoacetate. The hydroxybutyrate arises from acetoacetate by reduction. The overall sum of ketone body formation is the generation of acetoacetate (or hydroxybutyrate) and the freeing-up of the 2 CoAs that were trapped as acetyl-CoA. 

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