Cofactors Articles 1

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Riboswitch effectors as protein enzyme cofactors

            (Cochrane and Strobel 2008) Download

The recently identified glmS ribozyme revealed that RNA enzymes, like protein enzymes, are capable of using small molecules as catalytic cofactors to promote chemical reactions. Flavin mononucleotide (FMN), S-adenosyl methionine (SAM), adenosyl cobalamin (AdoCbl), and thiamine pyrophosphate (TPP) are known ligands for RNA riboswitches in the control of gene expression, but are also catalytically powerful and ubiquitous cofactors in protein enzymes. If RNA, instead of just binding these molecules, could harness the chemical potential of the cofactor, it would significantly expand the enzymatic repertoire of ribozymes. Here we review the chemistry of AdoCbl, SAM, FMN, and TPP in protein enzymology and speculate on how these cofactors might have been used by ribozymes in the prebiotic RNA World or may still find application in modern biology.

Esmond E. Snell--the pathfinder of B vitamins and cofactors

            (Hayashi, Tanase et al. 2011) Download

Esmond E. Snell (1914-2003) was a giant of B-vitamin and enzyme research. His early research in bacterial nutrition had lead to the discovery of vitamins such as lipoic acid and folic acid, and an anti-vitamin avidin. He developed microbiological assay methods for riboflavin and other vitamins and amino acids, which are still used today. He also investigated the metabolism of vitamins, discovered pyridoxal and pyridoxamine as the active forms of vitamin B(6) and revealed the mechanism of transamination and other reactions catalysed by vitamin B(6) enzymes. His research in later years on pyruvoyl-dependent histidine decarboxylase unveiled the biogenesis mechanism of this first built-in cofactor. Throughout his career, he was a great mentor of many people, all of whom are inspired by his philosophy of science.

Evolution of enzymes and pathways for the biosynthesis of cofactors

            (Holliday, Thornton et al. 2007) Download

The evolution of metabolic pathways is discussed with reference to the biosynthesis of a number of vitamins and cofactors. Retrograde and patchwork models are highlighted and their relevance to our knowledge of pathway processes and enzymes is examined. Pathway complexity is explained in terms of the acquisition of broad specificity enzymes.

Recent advances in ascorbate biosynthesis and the physiological significance of ascorbate peroxidase in photosynthesizing organisms

            (Ishikawa and Shigeoka 2008) Download

Ascorbate (AsA), the most abundant water-soluble redox compound in plants and eukaryotic algae, has multiple functions. There is compelling genetic evidence that the biosynthesis of AsA proceeds via a D-mannose/L-galactose pathway and is the most significant source of AsA in plants. AsA plays important roles in antioxidative defense, particularly via the AsA/glutathione cycle. AsA peroxidase (APX) plays a central role in the cycle and is emerging as a key enzyme in cellular H(2)O(2) metabolism. Plants possess diverse APX isoenzymes in cellular compartments, including the chloroplast, cytosol, and microbody. In algae, however, the number and distribution of APX proteins are quite limited. Recent progress in molecular biological analysis of APX isoenzymes has revealed elaborate mechanisms for the tissue-dependent regulation of two chloroplastic APX isoenzymes by alternative splicing, and for redox regulation of cytosolic APX gene expression in response to light stress. Furthermore, transgenic plants overexpressing a chloroplastic APX isoenzyme enable us to evaluate the behavior of the enzyme under conditions of photo-oxidative stress. Molecular physiological analysis has revealed that cytosolic APX is part of the system modulating the cellular H(2)O(2) level in redox signaling.

Editorial: vitamins and cofactors - chemistry, biochemistry and biology

            (Leeper and Smith 2007) Download

Vitamins and cofactors: highlights of ESBOC 2009

            (McDonald 2009) Download

On the enzymatic activation of NADH

            (Meijers, Morris et al. 2001) Download

Atomic (1 A) resolution x-ray structures of horse liver alcohol dehydrogenase in complex with NADH revealed the formation of an adduct in the active site between a metal-bound water and NADH. Furthermore, a pronounced distortion of the pyridine ring of NADH was observed. A series of quantum chemical calculations on the water-nicotinamide adduct showed that the puckering of the pyridine ring in the crystal structures can only be reproduced when the water is considered a hydroxide ion. These observations provide fundamental insight into the enzymatic activation of NADH for hydride transfer.

Metal and cofactor insertion

(Mendel, Smith et al. 2007) Download

Cells require metal ions as cofactors for the assembly of metalloproteins. Principally one has to distinguish between metal ions that are directly incorporated into their cognate sites on proteins and those metal ions that have to become part of prosthetic groups, cofactors or complexes prior to insertion of theses moieties into target proteins. Molybdenum is only active as part of the molybdenum cofactor, iron can be part of diverse Fe-S clusters or of the heme group, while copper ions are directly delivered to their targets. We will focus in greater detail on molybdenum metabolism because molybdenum metabolism is a good example for demonstrating the role and the network of metals in metabolism: each of the three steps in the pathway of molybdenum cofactor formation depends on a different metal (iron, copper, molybdenum) and also the enzymes finally harbouring the molybdenum cofactor need additional metal-containing groups to function (iron sulfur-clusters, heme-iron).

A genomic overview of pyridoxal-phosphate-dependent enzymes

            (Percudani and Peracchi 2003) Download

Enzymes that use the cofactor pyridoxal phosphate (PLP) constitute a ubiquitous class of biocatalysts. Here, we analyse their variety and genomic distribution as an example of the current opportunities and challenges for the study of protein families. In many free-living prokaryotes, almost 1.5% of all genes code for PLP-dependent enzymes, but in higher eukaryotes the percentage is substantially lower, consistent with these catalysts being involved mainly in basic metabolism. Assigning the function of PLP-dependent enzymes simply on the basis of sequence criteria is not straightforward because, as a consequence of their common mechanistic features, these enzymes have intricate evolutionary relationships. Thus, many genes for PLP-dependent enzymes remain functionally unclassified, and several of them might encode undescribed catalytic activities. In addition, PLP-dependent enzymes often show catalytic promiscuity (that is, a single enzyme catalyses different reactions), implying that an organism can have more PLP-dependent activities than it has genes for PLP-dependent enzymes. This observation presumably applies to many other classes of protein-encoding genes.

Roles of vitamins B5, B8, B9, B12 and molybdenum cofactor at cellular and organismal levels

            (Rebeille, Ravanel et al. 2007) Download

Many efforts have been made in recent decades to understand how coenzymes, including vitamins, are synthesised in organisms. In the present review, we describe the most recent findings about the biological roles of five coenzymes: folate (vitamin B9), pantothenate (vitamin B5), cobalamin (vitamin B12), biotin (vitamin B8) and molybdenum cofactor (Moco). In the first part, we will emphasise their biological functions, including the specific roles found in some organisms. In the second part we will present some nutritional aspects and potential strategies to enhance the cofactor contents in organisms of interest.

Coenzyme biosynthesis: enzyme mechanism, structure and inhibition

            (Scott, Ciulli et al. 2007) Download

This review highlights five key reactions in vitamin biosynthesis and in particular focuses on their mechanisms and inhibition and insights from structural studies. Each of the enzymes has the potential to be a target for novel antimicrobial agents.

Siroheme: an essential component for life on earth

            (Tripathy, Sherameti et al. 2010) Download

Life on earth is dependent on sulphur (S) and nitrogen (N). In plants, the second step in the reduction of sulphate and nitrate are mediated by the enzymes sulphite and nitrite reductases, which contain the iron (Fe)-containing siroheme as a cofactor. It is synthesized from the tetrapyrrole primogenitor uroporphyrinogen III in the plastids via three enzymatic reactions, methylation, oxidation and ferrochelatation. Without siroheme biosynthesis, there would be no life on earth. Limitations in siroheme should have an enormous effect on the S- and N-metabolism, plant growth, development, fitness and reproduction, biotic and abiotic stresses including growth under S, N and Fe limitations, and the response to pathogens and beneficial interaction partners. Furthermore, the vast majority of redox-reactions in plants depend on S-components, and S-containing compounds are also involved in the detoxification of heavy metals and other chemical toxins. Disturbance of siroheme biosynthesis may cause the accumulation of light-sensitive intermediates and reactive oxygen species, which are harmful, or they can function as signaling molecules and participate in interorganellar signaling processes. This review highlights the role of siroheme in these scenarios.

Elucidating biosynthetic pathways for vitamins and cofactors

            (Webb, Marquet et al. 2007) Download

The elucidation of the pathways to the water-soluble vitamins and cofactors has provided many biochemical and chemical challenges. This is a reflection both of their complex chemical nature, and the fact that they are often made in small amounts, making detection of the enzyme activities and intermediates difficult. Here we present an orthogonal review of how these challenges have been overcome using a combination of methods, which are often ingenious. We make particular reference to some recent developments in the study of biotin, pantothenate, folate, pyridoxol, cobalamin, thiamine, riboflavin and molybdopterin biosynthesis.


Cochrane, J. C. and S. A. Strobel (2008). "Riboswitch effectors as protein enzyme cofactors." RNA 14(6): 993-1002.

Hayashi, H., S. Tanase, et al. (2011). "Esmond E. Snell--the pathfinder of B vitamins and cofactors." J Biochem 147(4): 451-7.

Holliday, G. L., J. M. Thornton, et al. (2007). "Evolution of enzymes and pathways for the biosynthesis of cofactors." Nat Prod Rep 24(5): 972-87.

Ishikawa, T. and S. Shigeoka (2008). "Recent advances in ascorbate biosynthesis and the physiological significance of ascorbate peroxidase in photosynthesizing organisms." Biosci Biotechnol Biochem 72(5): 1143-54.

Leeper, F. J. and A. G. Smith (2007). "Editorial: vitamins and cofactors - chemistry, biochemistry and biology." Nat Prod Rep 24(5): 923-6.

McDonald, E. (2009). "Vitamins and cofactors: highlights of ESBOC 2009." Nat Chem Biol 5(8): 530-3.

Meijers, R., R. J. Morris, et al. (2001). "On the enzymatic activation of NADH." J Biol Chem 276(12): 9316-21.

Mendel, R. R., A. G. Smith, et al. (2007). "Metal and cofactor insertion." Nat Prod Rep 24(5): 963-71.

Percudani, R. and A. Peracchi (2003). "A genomic overview of pyridoxal-phosphate-dependent enzymes." EMBO Rep 4(9): 850-4.

Rebeille, F., S. Ravanel, et al. (2007). "Roles of vitamins B5, B8, B9, B12 and molybdenum cofactor at cellular and organismal levels." Nat Prod Rep 24(5): 949-62.

Scott, D. E., A. Ciulli, et al. (2007). "Coenzyme biosynthesis: enzyme mechanism, structure and inhibition." Nat Prod Rep 24(5): 1009-26.

Tripathy, B. C., I. Sherameti, et al. (2010). "Siroheme: an essential component for life on earth." Plant Signal Behav 5(1): 14-20.

Webb, M. E., A. Marquet, et al. (2007). "Elucidating biosynthetic pathways for vitamins and cofactors." Nat Prod Rep 24(5): 988-1008.