5-Deazaflavins reduction

Oxidative substitutions at ring junction positions in various tetrahydro-5-deaza-pterins (79JA6068) and -flavins (77JA6721) have been studied, e.g. to give (13), and the oxidation-reduction reactions of 5-deazaflavins (e.g. 78CL1177, 80CPB3514) across the 1,5-positions, e.g. (19) (20), are involved in their co-enzymic role in enzymic oxidations (see Section... 

Apart from the nuclear bromination observed (Section 2.15.13.1) in the attempted radical bromination of a side-chain methyl group leading to (396), which may or may not have involved radical intermediates, the only other reaction of interest in this section is a light-induced reduction of certain hydroxypyrido[3,4-f)]pyrazines or their 0x0 tautomers analogous to that well-known in the pteridine field (63JCS5156). Related one-electron reduction products of laser photolysis experiments with 1 -deazaflavins have been described (79MI21502). 

Reduction of A. vinosum hydrogenase in an ETIR cuvette by illumination in the presence of deazaflavin... 

Figure 1.11 Reduction of A. vinosum hydrogenase in an FTIR cuvette by illumination in the presence of deazaflavin. An Ar-flushed solution of enzyme in the ready state, supplemented with deazaflavin and EDTA, was illuminated with white light for periods of about 4 min. After each illumination a spectrum was recorded. Reduction proceeds from the front to the back. Using the overview in Fig. 7.6, one can easily identify the several states of the enzyme by looking at the v(CO) frequency. Adapted from (Pierik et al. 1998a).

By this time it was demonstrated that the [3Fe-4S]W+ form of aconitase is inactive, while the [4Fe-4S]2+ form is active. How is the activity of the enzyme affected by the oxidation state of the [4Fe-4S] cluster Because the active enzyme contains a [4Fe-4S]2+ cluster, either the 3+ or 1+ oxidation states may also be stable. The 3+ state is unstable since oxidation of the [4Fe-4S]2+ resulted in the immediate loss of a ferrous ion and conversion to a [3Fe-4S]i+ cluster (46,47). However, reduction of active aconitase by sodium dithionite or photoreduction in the presence of deazaflavin produced in high yields an EPR signal characteristic for [4Fe-4S]l+ clusters (47). When active enzyme within an anaerobic assay cuvette was photoreduced, the activity of the enzyme dropped to 1/3 of its initial value. Further photoreduction resulted in cluster destruction. Then, if the enzyme is reoxidized with air, the activity returned to its original value. This demonstrated that the redox state of the cluster can modulate the enzyme activity. A scheme summarizing the cluster interconversions and various redox states of the Fe-S cluster of aconitase is shown below. 

However, these experiments may not have established a mechanism for natural flavoprotein catalysis because the properties of 5-deazaflavins resemble those of NAD+ more than of flavins.239 Their oxidation-reduction potentials are low, they do not form stable free radicals, and their reduced forms don t react readily with 02. Nevertheless, for an acyl-CoA dehydrogenase the rate of reaction of the deazaflavin is almost as fast as that of natural FAD.238 For these enzymes a hydride ion transfer from the (3 CH (reaction type D of Table 15-1) is made easy by removal of the a-H of the acyl-CoA to form an enolate anion intermediate. 

The reductant is the deazaflavin F420 and the reactions parallel those for conversion of formyl-THF to methyl-THF (Fig. 15-18).431 440b 441 The methyl group of methyl-H4MPT is then transferred to the sulfur atom of the thiolate anion of coenzyme M, from which it is reduced off as CH4. This is a complex process requiring the nickel-containing F430,... 

The three-pulse electron spin-echo envelope modulation (ESEEM) technique is particularly sensitive for detecting hyperfine couplings to nuclei with a weak nuclear moment, such as 14N. It has been used to probe the coordination state of nickel in two hydrogenases from M. tkermoautotrophicum, strain AH (56). One of these enzymes contains FAD and catalyzes the reduction of F420 (7,8-dimethyl-8-hydroxy-5-deazaflavin), while the other contains no FAD and has so far only been shown to reduce artificial redox agents such as methyl viologen. 

The catalytic effect of metal ions such as Mg2+ and Zn2+ on the reduction of carbonyl compounds has extensively been studied in connection with the involvement of metal ions in the oxidation-reduction reactions of nicotinamide coenzymes [144-149]. Acceleration effects of Mg2+ on hydride transfer from NADH model compounds to carbonyl compounds have been shown to be ascribed to the catalysis on the initial electron transfer process, which is the rate-determining step of the overall hydride transfer reactions [16,87,149]. The Mg2+ ion has also been shown to accelerate electron transfer from cis-dialkylcobalt(III) complexes to p-ben-zoquinone derivatives [150,151]. In this context, a remarkable catalytic effect of Mg2+ was also found on photoinduced electron transfer reactions from various electron donors to flavin analogs in 1984 [152], The Mg2+ (or Zn2+) ion forms complexes with a flavin analog la and 5-deazaflavins 2a-c with a 1 1 stoichiometry in dry MeCN at 298 K [153] ... 

Subsequent to the synthesis of 5-carba-5-deaza- and 1-carba-1-deazariboflavin, the Merck group synthesized 1,5-dideazari-boflavin, XIV, with both redox-active nitrogens replaced by carbon (22). Some expected patterns of reactivity are observed. The reduction potential for two-electron reduction to the dihydro form, XV, has been estimated at —370 mV, an essentially additive effect from the two deazaflavins previously noted. This low value puts XIV out of the... 

Reduction of the derivatives (76) by a selenium-containing hydrogenase from Methanococcus vannielii gave the (R)-isomers (77) as confirmed by its degradation to (78) <85PNA(82)1364>. A direct hydride equivalent transfer from C-l of alcoholates to C-5 of 5-deazaflavins was confirmed by deuteration <87JHC25i>. 

Meanwhile we can show (50) that the deazaflavin radical generated by photodissociation of the dimer as shown in Figure 7 can be utilized for selective reduction of flavodoxin radical. With the aid of this le -transfer method Scherings, Haaker, and Veeger (51) were able to show that flavodoxin is the actual electron donor for the Azotobacter nitrogen-ase system and that N2 reduction can be maintained in the light by an artificial chain system of the reactant sequence EDTA-deazaflavin—flavodoxin—nitrogenase. Hence, Azotobacter flavodoxin is actually a carrier... 

Benzothiopyrano[2,3-c/]pyrimidines(5-deaza-10-thiaflavines) are of special biological interest because of their isosteric and isoelectronic structure to 5-desazaflavine. The synthesis starts from 6-chloro-5-formyl-3-meth-yluracil and thiophenol and subsequent cyclization of the phenylthio intermediate with PPA. Base-catalyzed reduction with secondary alcohols leads to a 5//-benzothiopyrano[2,3-fi(]pyrimidine (78TL2803 81JHC1329). 8-Substituted 5-deazaflavins have been made by a simple approach (cf. (85JHC841) (Scheme 101). 

---