3-Hydroxypropionate/4-hydroxybutyrate

The product of acetyl-CoA carboxylase reaction, malonyl-CoA, is reduced via malonate semialdehyde to 3-hydroxypropionate, which is further reductively converted to propionyl-CoA. Propionyl-CoA is carboxylated to (S)-methylmalonyl-CoA by the same carboxylase. (S)-Methylmalonyl-CoA is isomerized to (R)-methylmal-onyl-CoA, followed by carbon rearrangement to succinyl-CoA by coenzyme B 12-dependent methylmalonyl-CoA mutase. Succinyl-CoA is further reduced to succinate semialdehyde and then to 4-hydroxybutyrate. The latter compound is converted into two acetyl-CoA molecules via 4-hydroxybutyryl-CoA dehydratase, a key enzyme of the pathway. 4-Hydroxybutyryl-CoA dehydratase is a [4Fe-4S] cluster and FAD-containing enzyme that catalyzes the elimination of water from 4-hydroxybutyryl-CoA by a ketyl radical mechanism to yield crotonyl-CoA [34]. Conversion of the latter into two molecules of acetyl-CoA proceeds via normal P-oxidation steps. Hence, the 3-hydroxypropionate/4-hydroxybutyrate cycle (as illustrated in Figure 3.5) can be divided into two parts. In the first part, acetyl-CoA and two bicarbonate molecules are transformed to succinyl-CoA, while in the second part succinyl-CoA is converted to two acetyl-CoA molecules. 

The 3-hydroxypropionate/4-hydroxybutyrate cycle functions in autotrophic Sul-folobales (Crenarchaeota) [35-37]. These are extreme thermoacidophiles from volcanic areas which grow best at a pH of about 2 and temperatures of 60 to 90 °C. 

Figure 3.5 3-Hydroxypropionate/4-hydroxybutyrate cycle, as studied in Metaiiosphaera sedula.

The active C02 species in the 3-hydroxypropionate/4-hydroxybutyrate cycle is bicarbonate (see Table 3.1). The use of bicarbonate as a substrate may be advantageous for organisms using this cycle in comparison with, for example, the CBB... 

This cycle resembles the 3-hydroxypropionate/4-hydroxybutyrate cycle, but with pyruvate ferredoxin oxidoreductase (pyruvate synthase) and phosphoenolpyruvate (PEP) carboxylase as the carboxylating enzymes (Figure 3.6). 

The dicarboxylate/4-hydroxybutyrate cycle starts from acetyl-CoA, which is reductively carboxylated to pyruvate. Pyruvate is converted to PEP and then car-boxylated to oxaloacetate. The latter is reduced to succinyl-CoA by the reactions of an incomplete reductive citric acid cycle. Succinyl-CoA is reduced to 4-hydroxybu-tyrate, the subsequent conversion of which into two acetyl-CoA molecules proceeds in the same way as in the 3-hydroxypropionate/4-hydroxybutyrate cycle. The cycle can be divided into part 1 transforming acetyl-CoA, one C02 and one bicarbonate to succinyl-CoA via pyruvate, PEP, and oxaloacetate, and part 2 converting succinyl-CoA via 4-hydroxybutyrate into two molecules of acetyl-CoA. This cycle was shown to function in Igrticoccus hospitalis, an anaerobic autotrophic hyperther-mophilic Archaeum (Desulfurococcales) [40]. Moreover, this pathway functions in Thermoproteus neutrophilus (Thermoproteales), where the reductive citric acid cycle was earlier assumed to operate, but was later disproved (W.H. Ramos-Vera et al., unpublished results). 

W., and Fuchs, G. (2007) A 3-hydroxypropionate/4-hydroxybutyrate autotrophic carbon dioxide assimilation pathway in Archaea. Science, 318, 1782-1786. 

Acyl-CoA carboxylase pathways 3-hydroxypropionate/malonyl-CoA cycle [18, 19], 3-hydroxypropionate/4-hydroxybutyrate cycle [20], diearboxylate/ 4-hydroxybutyrate pathway [21], and the ethylmalonyl-CoA pathway [22]. 

For this reason (similar approach of conversion), it was assumed that both enzymes are identical [38]. In both cases a C2-unit is produced the acetyl-CoA in the 3-hydroxypropionate/malyl-CoA cycle and the glyoxylate in the 3-hydroxypropionate/4-hydroxybutyrate pathway. 

Figure 14.3 Production of 3-hydroxypropionic acid as a metabolic intermediate and an end product via 3-hydroxypropionate/4-hydroxybutyrate cycle in Metalhsphaera sedula. Enzymes accACD, acetyl-CoA carboxylase mcr, malonyl-CoA reductase.

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