Heterocyclic cofactors

SOME ASPECTS OF THE METABOLISM OF SULFUR-CONTAINING HETEROCYCLIC COFACTORS LIPOIC ACID, BIOTIN, AND 8a-(S-L-CYSTEINYL)RIBOFLAVIN... 

It will be the purpose of this chapter to provide an overview of our knowledge on the catabolism of three S-containing heterocyclic cofactors, viz. lipoate, biotin, and the 8a-(S-L-cysteinyl)riboflavin, with emphasis on the fate of the molecular sulfur others will deal with the more-biosynthetic aspects of lipoic acid and biotin. 

Methoxatin, now known as coenzyme PQQ, was originally obtained from methylotrophic bacteria but is now known to be a mammalian cofactor, for example, for lysyl oxidase and dopamine p-hydroxylase. The first synthesis of this rare compound was accomplished by the route outlined below. In the retrosynthetic analysis both of the heterocyclic rings were disconnected using directly keyed transforms. 

A number of molybdenum-containing hydroxylases catalyzing the first hydrox-ylation step of N-containing compounds have been characterized thoroughly (e.g., carbazole [314], quinoline [327], and indole [350]). The enzyme s redox-active has been described as a molybdenum ion site coordinated to a distinct pyranopterin cofactor (two different [2Fe2S] centers) and in most cases, flavin adenine dinucleotide centers. This active center transfers electrons from the N-heterocyclic substrate to an electron acceptor, which for many molybdenum hydroxylases is still unknown [350],... 

A number of nitrogen heterocyclic, aromatic compounds, riboflavin 26, folic acid 27a and biopterin 27b, isolated from natural sources, are related in structure to natural redox enzyme cofactors. The electrochemistry of these and related compounds has been studied extensively. 

FADH2 halogenases such as tryptophan 7-halogenase have been shown to catalyze regioselective halogenation of a wide range of indole derivatives and aromatic heterocycles, where a cofactor regeneration system has recently been developed to use only a catalytic amount of cofactors (Scheme 7.13) [52, 53]. 

The natural cofactor of the AAHs, BH4 (Scheme 2), is a heterocyclic compound chemically classified as a pteridine that includes a fused pyrimidine and pyrazine rings. As many other naturally occurring pteridines BH4 has a pterin structure, which includes an amino substituent in position 2 and an oxo group in position 4 of the pyrimidine ring. The term biopterin is reserved for pterins with a dihydroxypropyl group in position 6. 

Compounds with heterocyclic rings are inextricably woven into the most basic biochemical processes of life. If one were to choose a step in a biochemical pathway at random, there would be a very good chance that one of the reactants or products would be a heterocyclic compound. Even if this was not true, participation of heterocyclics in the reaction in question would almost be certain as all biochemical transformations are catalyzed by enzymes, and three of the twenty amino acids found in enzymes contain heterocyclic rings. Of these, the imidazole ring of histidine in particular would be likely to be involved histidine is present at the active sites of many enzymes and usually functions as a general acid-base or as a metal ion ligand. Furthermore, many enzymes function only in the presence of certain small non-amino acid molecules called coenzymes (or cofactors) which more often than not are heterocyclic compounds. But even if the enzyme in question contained none of these coenzymes or the three amino acids referred to above, an essential role would still be played by heterocycles as all enzymes are synthesized according to the code in DNA, which of course is defined by the sequence of the heterocyclic bases found in DNA. 

When FI is replaced by PQQ (pyrroloquinolinequinone), a novel heterocyclic o-quinone cofactor that was first isolated and identified from methanol dehydrogenase of methylotrophic bacteria in 1979 [68], the photochemical oxidation of benzyl alcohols occurs efficiently without HC104 in MeCN [69] ... 

S -transferase (GST), glutathione (GSH) being the cofactor. These heterocyclic systems are strong peroxidizing herbicides. 

In an attempt to mimic the function of these enzymes, PDC was derivatized with the flavin analogs 8-bromoacetyl- and 6-bromoacetyl-10-methylisoalloxazine (the heterocyclic core of flavin cofactors shown in equation 20 below). The former led to total... 

Fig. 17. Some examples of organic ligands acting as nicotinamide cofactor mimetics (141-143) with redox-active metals M bound to N-heterocyclic carbene (14), 1,2-diimine (15), and amide groups (16).

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