Vitamin enzyme responses

In the diet, vitamin B12 is bound to proteins. Although some release of protein-bound vitamin B12 begins in the mouth, most of the release occurs in the stomach on exposure of food to gastric acid (HC1) and the proteolytic enzyme pepsin. For this reason, either hypo-chlorhydria (abnormally low concentration of HC1 in gastric fluid) or achlorhydria (the absence of HC1 in gastric fluid) may decrease the availability of dietary vitamin B12 for absorption by preventing the activation of pepsinogen to pepsin, the principal enzyme responsible for proteolysis in the stomach. Achlorhydric patients with adequate production of IF may have low normal or subnormal serum B12 concentrations because of failure to liberate B12 bound to food. 

Cystathionine /3-synthetase contains heme as well as pyridoxal phosphate, but this seems to have a regulatory rather than catalytic role the yeast enzyme does not contain heme (Jhee et al., 2000 Kabil et al., 2001). A common genetic polymorphism in human cystathionine /S-synthetase (a 68-base-pair insertion, occurring in about 12% of the general population) is associated with a lower than normal increase in plasma homocysteine after a methionine load in patients with low vitamin Be status, suggesting that the variant enzyme may have higher affinity for its cofactor than the normal form - the reverse of the position in the vitamin Bg responsive genetic diseases discussed in Section 9.4.3 (Tsaietal., 1999). 

Table 9.4 Vitamin Be-Responsive Inborn Errors of Metabolism Enzyme Affected EC No.

The major function of the K vitamins is in the maintenance of normal levels of the blood clotting proteins, factors II, VII, IX, X and protein C and protein S, which are synthesized in the liver as inactive precursor proteins. Conversion from inactive to active clotting factor requires a post-translational modification of specific glutamate (E) residues. This modification is a carboxylation and the enzyme responsible for it requires vitamin K as a cofactor. 

Enzymic catalysis of a rearrangement reaction has special mechanistic fascination and, for vitamin B12, a methyl group at C-11 of 66 shifts to C-12 of 60, Scheme 25. This step clears the blockage to movement of the double bonds so tautomerisation can now occur, with thermodynamic gain, to form the extended conjugated system of hydrogenobyrinic acid 60. The enzyme responsible for... 

The enzyme responsible for carbon dioxide fixation is called acetyl-CoA carboxylase and is dependent upon the presence of the metal ion manganese and also the vitamin biotin. In fact it is the biotin that first reacts with the C02 in an energy-requiring reaction that is driven by the simultaneous breakdown of ATP. The car-boxybiotin which is formed cab now be thought of as an activated carrier molecule, very similar to UDPG. It can easily transfer its C02 to acetyl CoA to give malony 1 CoA in the following reactions ... 

Approximately 10% of patients require <1.5 mg/day of warfarin to achieve an INR of 2—3. These patients are more likely to possess one or two polymorphic alleles of CYP2C9, the major enzyme responsible for converting the S-enantiomer warfarin to its inactive metabolites. In comparison with the wild-type CYP2C9 1 allele, the variant alleles CYP2C9 2 and CYP2C9 3 have been shown to inactivate S-warfarin much less efficiently in vitro. The variant alleles are present in 10-20% of Caucasians, but in <5% of African Americans or Asians. Polymorphic variations in VKORCl, which encodes a component of the Vitamin K reductase complex (see Figure 54-6), also determine warfarin sensitivity. 

The metabolic role of many minerals and vitamins is as prosthetic groups or coenzymes in different enzyme systems. Consequently, mineral and vitamin deficiencies can cause a breakdown of the processing system and precipitate metabolic disease. For example, methylmalonyl-CoA isomerase (see p. 203) is an important vitamin Bi2-dependent enzyme in the gluconeogenic pathway. A deficiency of vitamin B12 (or cobalt) may reduce enzyme activity, decrease the efficiency of glucose synthesis and predispose the animal to ketosis. Similarly, ceruloplasmin is a copper-dependent enzyme responsible for releasing iron from cells into blood plasma. A copper deficiency may reduce ceruloplasmin activity, decrease the efficiency of iron utilisation for haemoglobin synthesis and predispose the animal to anaemia. 

The present book is the second of two volumes that provide state of the art expert reviews of central topics in modern natural products chemistry and secondary metabolism. Using specific examples, the previous volume emphasized two revolutions in experimental techniques that completely transformed the field of natural products chemistry from what it was in the 1950s. These were the use of stable isotopes in conjunction with modern NMR and mass spectrometry, and more recently, the development of molecular biological techniques to identify, purify and manipulate the enzymes responsible for the intricate series of steps to complex natural compounds. The previous volume specifically covered the use of isotopes in biosynthetic research and the formation of enzyme cofactors, vitamin B12 and reduced polyketides. 

Faijo, K. M., G. Moiseyev, O. Nikolaeva, et al. 2011. RdhlO Is the Primary Enzyme Responsible for the First Step of Embryonic Vitamin A Metabolism and Retinoic Acid Synthesis. Dev Biol 357, no 2 347-55. 

What is the likelihood that retinitis pigmentosa is associated with a defect in the transport of vitamin A within the ocular tissues or in an enzyme responsible for its isomerization or conversion to one of its derivatives Some of the evidence against this view depends on comparisons between retinitis pigmentosa patients... 

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