Coenzyme biosynthesis

The requirement for vitamins in humans and other animals is the result of mutations in the enzymes involved in biosynthetic coenzymes. As intermediates of coenzyme biosynthesis are available in suf cient amounts in the diet of heterotrophic animals (see p. 112), the lack of endogenous synthesis did not have unfavorable effects for them. Microorganisms and plants whose nutrition is mainly autotrophic have to produce all of these compounds themselves in order to survive. 

Whereas plants and certain microorganisms can generate all required coenzymes from CO2 or simple organic precursors, animals must obtain precursors (designated as vitamins) for a major fraction of their coenzymes from nutritional sources. Still, most vitamins must be converted into the actual coenzymes by reactions catalyzed by animal enzymes. The structures and biosynthetic pathways of some coenzymes are characterized by extraordinary complexity. Enzymes for coenzyme biosynthesis have frequently low catalytic rates, and some of them catalyze reactions with highly unusual mechanisms. 

Many coenzymes (cofactors) involved in human and animal metabolism were discovered in the first half of the twentieth century, and their isolation and structure elucidation were hailed as milestones as shown by the impressive number of Nobel prizes awarded for research in that area. Studies on coenzyme biosynthesis were typically initiated in the second half of the twentieth century and have generated a massive body of literature that continues to grow rapidly because the area still involves many incompletely resolved problems. In parallel, numerous novel coenzymes were discovered relatively recently by studies of microorganisms. In this article, the terms cofactor and coenzyme are used as synonyms. 

In bacteria, coenzyme biosynthesis is located in the cytoplasm. In eukaryotic cells, organelles play important roles in the biosynthesis of certain cofactors. For example, certain steps of iron/sulfur cluster biosynthesis proceed in mitochondria... 

Three-dimensional structures of coenzyme biosynthesis enzymes... 

The rapid technological progress in X-ray crystallography has enabled the structural analysis of numerous enzymes involved in coenzyme biosynthesis. Complete sets of structures that cover all enzymes of a given pathway are available in certain cases such as riboflavin, tetrahydrobiopterin, and folic acid biosynthesis. Stmctures of orthologs from different taxonomic groups have been reported in certain cases. X-ray structures of enzymes in complex with substrates, products, and analogs of substrates, products, or intermediates have been essential for the elucidation of the reaction mechanisms. Structures of some coenzyme biosynthesis enzymes have been obtained by NMR-structure analysis. 

The rapidly growing number of three-dimensional coenzyme biosynthesis enzyme stmctures in the public domain and the cognate publications are best addressed via the internet server of Brookhaven Protein Data Bank (http /Avww.rcsb.org/pdb/home/ home.do). Queries can be targeted to individual enzymes or to entire pathways. 

Coenzyme biosynthesis enzymes as anti-infective drug targets... 

Drug interaction with coenzyme biosynthesis pathways... 

Scott DE, Ciulli, Abell C. Coenzyme biosynthesis enzyme mechanism, strucmre and inhibition. Nat. Prod. Rep. 2007 24 1009-1026. 50. 

The evolutionary relationships between these two pathways were cemented by the determination of the three-dimensional structure of ThiS, which revealed a structure very similar to that of ubiquitin, despite being only 14% identical in amino acid sequence (Figure 23.10). Thus, a eukaryotic system for protein modification evolved from a preexisting prokaryotic pathway for coenzyme biosynthesis. 

The pentose-phosphate pathway, also known as the hexose monophosphate pathway, is a metabolic system with two important consequences. The first is production of NADPH for biosynthesis, and the second is production of ribose-5-phosphate for nucleotide and coenzyme biosynthesis (Fig. 12.5). 

Laura L. Grochowski was born in Bedford, Pennsylvania, USA, in 1975 and received a BS in Biology from Delaware Valley College in 1997. She studied antibiotic and nonribosomal peptide biosynthesis with Mark Zabriskie at Oregon State University where she obtained a Ph.D. in Medicinal Chemistry in 2004. Laura then joined Bob White s lab in the Department of Biochemistry at Virginia Tech as a postdoctoral associate. Her work focuses on the uncanonical biochemistry and coenzyme biosynthesis of methanogenic archaea. 

Yang, Y. et al. (1998) Involvement of the gapA- and epd (gapB)-encoded dehydrogenases in pyridoxal 5 -phosphate coenzyme biosynthesis in Escherichia coli K-12. /. Bacterid., 180 (16), 4294-4299. 

Purines are not only the essential building blocks for nucleic acid and coenzyme biosynthesis, but purine... 

Until a few years ago I would have been reluctant to name DNA polymerase my favorite. The sentiment that goes to the first born was a strong attachment to DPN pyrophos-phorylase. It opened the door to coenzyme biosynthesis and the mystery of inorganic pyrophosphate. And it led me to the enzymatic synthesis of nucleotides and nucleic acids. 

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