Metabolic Aspects

Among all the steps involved in PHA biosynthesis and degradation, three enzymatic reactions are the central switch points where activation or inhibition on the enzyme activity shifts the carbon flux towards protein formation, PHA biosynthesis or PHA degradation. 

Polyhydroxyalkanoates biosynthesis is regulated, on one hand, by the activity of 3-ketothiolase (EC 2.3.1.16), and on the other hand of acetoacetyl-CoA reductase (EC 1.1.1.36) intracellular PHA breakdown is dependent on the activity of 3-hydroxybutyrate dehydrogenase (EC 1.1.1.30). Besides these three enzymes, the following compounds can be pointed out as major factors responsible of the activities of the key enzymes acetyl-CoA, free CoA, NAD(P) + (or NAD(P)H2, respectively) and, to a lower extent, ATP, pyruvate and oxalacetate. In any case, acetyl-CoA can be considered as the central metabolite both for biomass formation and PHB biosynthesis. This compound stems from the catabolic break down of carbon substrates like sugars (mainly catabolized by the 2-Keto-3-desoxy-6-phosphogluconate pathway) or fatty acids (converted by 6-oxidation). 

Catabolism via e.g. 2-keto-3-desoxy-6-phosphogluconate pathway (KDPa) 

Free CoA is inhibiting 3-ketothiolase as a consequence, the carbon flux towards PHAs is decreased. To a lower extent, 3-ketothiolase is also inhibited by NAD+ and ATP. Additionally, high amounts of NAD + slow down the reduction steps from acetoacetyl-CoA to 3-hydroxybutyryl-CoA by acetoacetyl-CoA reductase. 

Poly([f ]-3-hydroxybutyrate) degradation is regulated by inhibition of the oxidative conversion of 3-hydroxybutyrate to acetoacetate. Here, NADH2, pyruvate and oxalacetate act as inhibitors. The last step, the splitting of acetoacetyl-CoA into two acetyl-CoA molecules by 3-ketothiolase, is product inhibited by high concentrations of acetyl-CoA. High concentrations of free CoA, the second substrate of this cleaving reaction, relieve this product inhibition [28]. 

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Volume 189. Retinoids (Part A Molecular and Metabolic Aspects)... 

Kunz, C., Rudloff, S., Baier, W., Klein, N., and Strobel, S. (2000). Oligosaccharides in human milk Structural, functional, and metabolic aspects. Annu. Rev. Nutr. 20, 699-722. 

Remer, T. (2001). Influence of nutrition on acid-base balance—metabolic aspects. Eur. J. Nutr. 40, 214-220. 

Skouby SOCommittee Chairman. Consensus Development Meeting Metabolic aspects of oral contraceptives of relevance for cardiovascular diseases. Am J Obstet Gynecol 1990 162 1335. 

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