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Micronutrients
Published in Chuong Pham-Huy, Bruno Pham Huy, Food and Lifestyle in Health and Disease, 2022
Chuong Pham-Huy, Bruno Pham Huy
In general, an enzyme cannot function alone; it must be activated by one or many small molecules called coenzymes and cofactors. Some enzymes require several coenzymes and cofactors. Coenzymes and cofactors are small organic molecules or metal ions that are used by enzymes to help catalyze reactions (89–93). In other words, coenzymes are typically organic molecules that contain functionalities not found in proteins, while cofactors are catalytically essential molecules or ions that are covalently bound to enzymes (91). The term holoenzyme refers to an active enzyme complex: an enzyme combined with a coenzyme or a cofactor. An apoenzyme is an inactive enzyme: an enzyme without an activator (coenzyme or/and cofactor). The term prosthetic group is used to refer to minerals, activated vitamins, or other nonprotein compounds that are required for full enzyme activity (89–93). The prosthetic group remains bonded for the enzyme during the reaction. In some cases, the prosthetic group is covalently bound for its apoenzyme, while in other cases it is weakly bound to the active center by numerous weak interactions (93).
Multiple carboxylase deficiency/biotinidase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Biotin, as a vitamin, cannot be synthesized by humans, but in addition to dietary sources, it is synthesized by intestinal microflora. There are dietary sources of free biotin, but covalently bound biotin must ultimately be acted upon by biotinidase to make biotin available from either dietary, intestinal bacterial or recycled sources (Figures 7.1 and 7.2). Biotin is an intrinsic cofactor for each of the carboxylase enzymes, which are synthesized as inactive apoenzymes and must be linked with biotin in the holocarboxylase synthetase reaction (Chapter 5) to become active holoenzymes.
Transcriptionally Regulatory Sequences of Phylogenetic Significance
Published in S. K. Dutta, DNA Systematics, 2019
Escherichia coli is a natural host for bacteriophage. As has been amply documented, its RNA polymerase is larger and more complex than that of the phage, consisting of several subunits (α2, β, βʹ) totaling about 355,000 daltons.2 The precise recognition of promoters by this core polymerase requires an additional polypeptide, the sigma factor. Together, these polypeptide units constitute the polymerase holoenzyme.
Potential therapeutic targets for Mpox: the evidence to date
Published in Expert Opinion on Therapeutic Targets, 2023
Siddappa N Byrareddy, Kalicharan Sharma, Shrikesh Sachdev, Athreya S. Reddy, Arpan Acharya, Kaylee M. Klaustermeier, Christian L Lorson, Kamal Singh
VACV DNA genome replication is conducted by a holoenzyme consisting of multiple proteins [25]. An essential component of this holoenzyme is E9, the DNA-dependent DNA polymerase belonging to B family DNA polymerases. The MPXV genome encodes F8L (OPG71) [2], also a B family DNA-dependent DNA polymerase [27], which shares ~ 98% identity with VACV E9. The first B family DNA polymerase (RB69) structure showed an overall architecture of this class of enzymes [28]. This structure showed a canonical polymerase domain consisting of the Thumb, Palm, and Fingers subdomains, as seen in the structure of the Klenow Fragment (KF) of E. coli DNA polymerase I [29]. A notable difference between these polymerases is the relative position of the 3’ − 5’ exonuclease domain, which is ~ 180° opposite to that in KF relative to the polymerase active site. Subsequent crystal structures of the RB69 polymerase showed that residues of a β-hairpin positioned in the major groove of the template-primer played a role in the partitioning of primer to the 3’ − 5’ exonuclease site upon mismatch nucleotide incorporation [28,30–32]. Indeed, a resistance mutation on topologically similar β-hairpin in poxviruses’ DNA polymerase showed the relevance of the resistance mechanism of nucleotide analogs mediated by 3’ − 5’ exonuclease function (discussed below).
Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Bianka Edina Herman, Anita Kiss, János Wölfling, Erzsébet Mernyák, Mihály Szécsi, Gyula Schneider
Cofactor-dependent affinities of some of the investigated compounds indicate that binding capabilities of the binding hole may be different depending on the nature of cofactor the enzyme complexed with. The binding hole suitable to accommodate C15 side chains is known to be formed by amino acids Leu96, Met193, Gly198, Tyr218, Leu219, and Ser22212. Residues Met193 and Gly198 are also constituents of the disordered loop (amino acids 189–200) which adopt a specific conformation following cofactor binding25,27. The presence or absence of 2′-phosphate in the cofactors causes differences in the structure of the holoenzymes. Furthermore, the area of the substrate binding site may also be affected in a different way in these complexes25,27,31. We may also assume that binding of NADPH or NADH modifies the conformation of the loop of residues 189–200 differently. Joint residues Met193 and Gly198 of the two structural elements transmit this difference from the loop to the binding hole, and these processes induce different positioning and binding capabilities of the binding hole in the holoenzyme variants. Hosting certain C15 side chains, therefore, might be, therefore, favoured or unfavoured in the binding hole altered differently upon binding of phosphorylated or unphosphorylated cofactors.
Structure-guided design of anti-cancer ribonucleotide reductase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Tessianna A. Misko, Yi-Ting Liu, Michael E. Harris, Nancy L. Oleinick, John Pink, Hsueh-Yun Lee, Chris G. Dealwis
Human ribonucleotide reductase (hRR) is a ubiquitous multi-subunit enzyme that is crucial for cell division and DNA repair1–4. RR catalyses the rate-determining step of dNTP synthesis by removing the 2′ hydroxyl of the ribose to generate a deoxyribose1. RR is critical for the maintenance of a balanced nucleotide pool in cells where imbalances lead to mutator phenotypes1,5,6. RR activity is maintained under tight regulation at the levels of transcription7, allostery1, cellular localisation8, and enzyme inhibition by Sml1 in Saccharomyces cerevisiae9. hRR is a multi-subunit enzyme consisting of a large subunit hRRM1, containing a catalytic site (C-site) and two allosteric sites known as the specificity site (S-site) and the activity site (A-site)1 (Figure 1). hRRM1 associates with the small subunit hRRM2 that houses a free radical essential for catalysis to form the holoenzyme10. ATP and dATP bind the A-site, inducing active and inactive hexamers, respectively11. Binding of dGTP, dTTP, dATP, or ATP to the S-site not only induces dimerisation of hRRM1 but also acts as a selection gate, regulating the relative Kcat/Km for the four NDP substrates: ADP, GDP, CDP, or UDP, respectively1.