Y-Butyrobetaine

A number of iron-containing, ascorbate-requiring hydroxylases share a common reaction mechanism in which hydroxylation of the substrate is linked to decarboxylation of a-ketoglutarate (Figure 28-11). Many of these enzymes are involved in the modification of precursor proteins. Proline and lysine hydroxylases are required for the postsynthetic modification of procollagen to collagen, and prohne hydroxylase is also required in formation of osteocalcin and the Clq component of complement. Aspartate P-hydroxylase is required for the postsynthetic modification of the precursor of protein C, the vitamin K-dependent protease which hydrolyzes activated factor V in the blood clotting cascade. TrimethyUysine and y-butyrobetaine hydroxylases are required for the synthesis of carnitine. 

In a somewhat ambiguous manner crotonbetaine, (CH3)3 N+ CH2 -CH=CH COO- and carnitin, (CH3)3 N+ CH2 CHOH CH2 COO- were hydrogenated to y-butyrobetaine, (CH3)3 N+-CH2-CH2-CH2-COO , by undefined mixtures of bacteria of putrefying pancreas in the presence of D-glucose after the long time of four months. ... 

Carnitine, L-3-hydroxy-4-(trimethylammonium)butyrate, is a water-soluble, tri-methylammonium derivative of y-amino-jS-hydroxybutyric acid, which is formed from trimethyllysine via y-butyrobetaine [40]. About 75% of carnitine is obtained from dietary intake of meat, fish, and dairy products containing proteins with trimethyllysine residues. Under normal conditions, endogenous synthesis from lysine and methionine plays a minor role, but can be stimulated by a diet low in carnitine. Carnitine is not further metabolized and is excreted in urine and bile as free carnitine or as conjugated carnitine esters [1, 41, 42]. Adequate intracellular levels of carnitine are therefore maintained by mechanisms that modulate dietary intake, endogenous synthesis, reabsorption, and cellular uptake. 

The mechanism of a-ketoglutarate participation in the dioxygenase reaction has been proposed by Lindstedt and his co-workers6S,220) as shown in Eq. (27) with y-butyrobetaine hydroxylase. 

L. Boehlen, and I. Psenicka, Process integration aspeds for the production of fine chemicals illustrated with the biotransformation of y-butyrobetaine into L-camitine, Chem. Eng.J. 1996, 63, 53-61. 

In general, the effects on collagen synthesis are more marked and more important than those of decreased formation of carnitine (as a result of impaired activity of trimethyllysine and y-butyrobetaine hydroxylases Section 14.1.1), impaired xenobiotic metabolism, or hypercholesterolemia (Section 13.3.8). However, depletion of muscle carititine may account for the lassitude and fatigue that precede clinical signs of scurvy. 

In general, the effects on collagen synthesis are more marked and more important than those of decreased formation of carnitine (as a result of impaired activity of trimethyllysine and y-butyrobetaine hydroxylases Section... 

Figure 14.2. Biosynthesis of carnitine. Trimethyllysine hydroxylase, EC 1.14.11.8 aldolase, EC 4.1.2. x aldehyde dehydrogenase, EC 1.2.1.47 y-butyrobetaine hydroxylase, EC 1.14.11.1. Relative molecular mass (Mr) carnitine, 161.2.

An example of a process where the fed-batch mode has a decisive advantage over a continuous operation is the biotransformation of y-butyrobetaine into L-carnitine. This fine chemical has pharmacological, nutritional, and animal-feed applications, making product purification an essential part of the production process. Consequently, process optimization of biotransformation and downstream... 

L-Malate L-Camitine Fumarate y-Butyrobetaine Fumarase An enoyl-CoA hydra tase 500 tons Started... 

In addition to collagen metabolism and scavenging ROS species to limit inflammation as noted above, ascorbate is required for the synthesis of norepinephrine from tyrosine, of carnitine from y-butyrobetaine whose immediate precursor is made by trimethylating lysine, for folinic acid production from folic acid. In the absence of ascorbate, the reduced activity of these processes slows nerve, energy and cardiac output, causingthe affected person to become exhausted and irritable. Scurvy is the old English word for ill-tempered. 

In this manner, y-butyrobetaine hydroxylase catalyzes the terminal step in carnitine biosynthesis, the hydroxylation of 4-A(-trimethyl-aminobutyrate. a-Kctoglutaratc-dcpendent dioxygenases act as oxygenation catalysts only in the presence of iron ions. Formation of thermodynamically stable CO2 helps to produce a high-valent center (Scheme XI. 12) [38a]. 

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