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Prosthetic group

A prosthetic group is a tightly bound, non-amino acid component of a conjugated protein, such as an enzyme or transport protein, that is essential for its biological function and often remains attached even after denaturation.^[1] These groups are distinguished from loosely associated cofactors or coenzymes by their permanent or covalent attachment to the protein's apoenzyme (the protein without the group), forming a holoenzyme that exhibits full activity.^[2] Prosthetic groups can be organic molecules derived from vitamins, carbohydrates, or lipids, or inorganic elements like metal ions, and they typically facilitate processes such as catalysis, electron transfer, or substrate binding.^[1] In enzymes, prosthetic groups play a critical role by providing reactive sites or structural elements necessary for function; for instance, the heme group, an iron-containing porphyrin ring, serves as the prosthetic group in hemoproteins like myoglobin and hemoglobin, enabling oxygen binding and transport.^[1] Other notable examples include biotin, which covalently attaches to carboxylases via a lysine residue to aid in carboxylation reactions, and flavin adenine dinucleotide (FAD), an organic prosthetic group in oxidoreductases that participates in redox reactions.^[2] Inorganic prosthetic groups, such as zinc in carbonic anhydrase^[1] or magnesium in chlorophyll (a photosynthetic protein complex),^[3] often stabilize active sites or mediate metal-dependent catalysis. The incorporation of prosthetic groups into proteins can occur co- or post-translationally, sometimes requiring specific enzymes for attachment, as seen with heme lyases that covalently link heme to apocytochromes in mitochondrial electron transport chains.^[4] This tight binding enhances protein stability and specificity, but removal—via harsh treatments like silver salt extraction—renders the protein inactive, underscoring their indispensability.^[2] Prosthetic groups are ubiquitous in biochemistry, contributing to diverse physiological processes from respiration and photosynthesis to metabolic regulation.^[5]

Definition and Terminology

Definition

A prosthetic group is defined as a tightly bound, non-amino acid molecular component, either organic or inorganic, that becomes a permanent part of conjugated proteins, especially enzymes, and is essential for their biological activity.^[6]^[7]^[8] These groups are distinguished by their strong, often covalent or non-covalent yet stable, association with the protein, enabling functions that the polypeptide chain alone cannot perform.^[9] In protein nomenclature, the fully functional assembly consisting of the protein and its prosthetic group is termed a holoprotein, whereas the protein devoid of this group is called an apoprotein, which is typically inactive or lacks full functionality.^[10]^[11]^[12] This distinction highlights the prosthetic group's indispensable role in achieving the native, active conformation of the protein.^[8] Representative examples of conjugated proteins include hemoproteins, which incorporate heme as their prosthetic group for oxygen transport and storage; flavoproteins, featuring flavin derivatives for redox reactions; and metalloproteins, which utilize metal ions like iron or zinc for catalytic purposes.^[10]^[13] Prosthetic groups are commonly derived from vitamins (such as flavins from vitamin B2), sugars, lipids, or inorganic metal ions, but they are invariably integrated into the protein's native three-dimensional structure to exert their effects.^[8]^[14]

Historical Background

The concept of the prosthetic group emerged in late 19th- and early 20th-century protein chemistry as a way to describe the non-protein components essential to the structure and function of conjugated proteins, analogous to a "prosthesis" that augments the protein's capabilities.^[15] The term "prosthetic group" was coined by biochemist Albrecht Kossel around 1900.^[16] It first appeared in scientific literature around 1895–1900, reflecting growing recognition of proteins as complex assemblies rather than simple polypeptides, with studies on substances like hemoglobin highlighting tightly bound, non-amino acid moieties.^[15] This development was intertwined with foundational work in protein chemistry, including Emil Fischer's investigations into peptide synthesis and protein linkages in the 1900s.^[17] Early discoveries of specific prosthetic groups began in the mid-19th century, with Felix Hoppe-Seyler's isolation and naming of hemoglobin in 1864, where he identified its red pigment as a bound iron-containing component crucial for oxygen transport.^[18] Hoppe-Seyler's spectroscopic analyses in the 1860s and 1870s revealed hemoglobin's distinct absorption bands, leading to the broader appreciation of non-protein groups permanently associated with proteins, though the term "prosthetic" was not yet formalized.^[19] These observations shifted focus from isolated proteins to conjugated forms, setting the stage for enzyme studies in the early 20th century. The concept evolved significantly in the 1920s and 1930s through investigations into enzyme catalysis and vitamin-derived cofactors, transitioning from descriptive terminology to a standardized framework. Otto Warburg's work in the 1930s exemplified this, as he isolated flavin mononucleotide (FMN) as the yellow prosthetic group in the "old yellow enzyme" from yeast, demonstrating its tight binding and role in cellular respiration.^[20] Warburg and Walter Christian's 1932 discovery of flavoproteins further solidified the prosthetic group as a distinct category, influenced by vitamin discoveries like riboflavin, which provided organic moieties for enzyme activity. By the 1950s, prosthetic groups had become central to elucidating enzyme mechanisms, as evidenced in Albert Lehninger's research on mitochondrial oxidative phosphorylation, where groups like heme in cytochromes were key to energy transduction pathways.^[21]

Characteristics and Binding

Key Characteristics

Prosthetic groups encompass both organic and inorganic components that are integral to the structure and function of conjugated proteins. Organic prosthetic groups are frequently derived from vitamins or other biomolecules, such as flavin mononucleotide (FMN) synthesized from riboflavin (vitamin B2), while inorganic ones include metal ions like Fe²⁺ and Zn²⁺ that coordinate within protein active sites.^[22]^[1] These groups are non-peptide in nature and distinguish themselves through their tight integration, often via covalent or coordinate bonds, which contrasts with more transient associations in proteins.^[2] A defining feature of prosthetic groups is their stability and permanence within the protein structure. Unlike loosely bound cofactors, they resist removal by dialysis or mild denaturation treatments, remaining associated even under conditions that dissociate weaker interactions.^[23] This durability contributes to protein folding and overall stability, as the prosthetic group often stabilizes the tertiary or quaternary conformation of the apoprotein (the protein without the group).^[1] Prosthetic groups are essential for the protein to attain its native, active conformation, enabling the holoprotein (the complete functional unit) to perform its biological roles.^[24] Prosthetic groups exhibit remarkable diversity in size and complexity, ranging from simple metal ions with atomic masses under 100 Da to elaborate organic structures like heme, a porphyrin ring complexed with iron exceeding 600 Da.^[1] They typically comprise a minor fraction of the holoprotein's mass, often 1-10%, as exemplified by the four heme groups in hemoglobin, which account for approximately 4% of its total molecular weight.^[25] This variability allows prosthetic groups to adapt to diverse protein environments while maintaining efficiency. Prosthetic groups are ubiquitous across all domains of life, from bacteria and archaea to eukaryotes, where they are indispensable for core metabolic processes such as electron transfer and catalysis.^[26] Iron-sulfur clusters, for instance, represent ancient prosthetic groups found in nearly all organisms, underscoring their evolutionary conservation and fundamental role in sustaining life.^[27]

Binding Mechanisms

Prosthetic groups bind to proteins through a variety of chemical interactions that ensure their stable integration, often rendering the association irreversible under physiological conditions. Covalent binding represents one primary mechanism, involving direct chemical bonds between the prosthetic group and specific amino acid residues in the protein. For instance, in c-type cytochromes, the heme prosthetic group forms two thioether bonds between its vinyl groups and the sulfur atoms of cysteine residues within a CXXCH motif, stabilizing the complex during electron transfer processes.^[28] Similarly, nucleotide-based prosthetic groups, such as 2'-(5''-phosphoribosyl)-3'-dephospho-CoA in the acyl carrier protein subunit of citrate lyase, attach via phosphodiester linkages to serine residues, facilitating acyl group transfer in metabolic pathways.^[29] Another example is lipoic acid, which covalently links to lysine residues through an amide bond in the E2 subunits of 2-oxoacid dehydrogenase complexes, enabling its role in redox reactions.^[30] Other covalent mechanisms include Schiff base formation, as in pyridoxal 5'-phosphate (PLP), where the aldehyde group of PLP reacts with the ε-amino group of a lysine residue to form an imine linkage, essential for amino acid transamination in enzymes like aspartate aminotransferase.^[31] In addition to covalent attachments, coordinate binding provides a tight, non-covalent mechanism, particularly for metal-containing prosthetic groups, where metal ions interact with electron donor atoms from protein side chains. This often involves coordination via nitrogen or oxygen atoms, as seen in heme proteins where the iron atom forms a coordinate bond with the imidazole nitrogen of a proximal histidine residue, contributing to oxygen binding and transport in hemoglobin.^[32] Such interactions are strengthened by the dative nature of the bond, where the ligand donates electrons to the metal center, resulting in high stability without full covalent character. The stability of these bindings is influenced by environmental factors such as pH, which can modulate protonation states of coordinating residues; redox conditions, affecting the oxidation state of metal ions or disulfide-containing groups; and protein conformation, which positions the binding site precisely.^[33] These factors collectively ensure that dissociation is minimal during catalytic cycles, with high binding free energies (often 50-100 kJ/mol or more), far surpassing those of loosely associated cofactors and preventing loss under physiological stresses.^[34]^[35]

Versus Cofactors and Coenzymes

Cofactors represent a broad class of non-protein chemical entities essential for enzyme activity, serving as helpers that enable or enhance catalysis. These include both organic molecules, such as coenzymes derived from vitamins, and inorganic components like metal ions. Prosthetic groups form a specific subset of cofactors characterized by their tight, often covalent binding to the enzyme, distinguishing them from more loosely associated cofactors. In contrast, coenzymes are typically organic cofactors that act as transient carriers, diffusing between enzymes and undergoing repeated cycles of modification and regeneration, as exemplified by nicotinamide adenine dinucleotide (NAD⁺), which shuttles electrons in redox reactions.^[6]^[36] The permanence of prosthetic groups contrasts sharply with the dynamic nature of coenzymes; while coenzymes bind reversibly and are released after facilitating a reaction, prosthetic groups remain integral to the enzyme structure throughout its functional lifecycle. This tight integration often results in the prosthetic group becoming a fixed component of the holoenzyme, the complete active form of the enzyme. For instance, metal ions like zinc or magnesium may serve as loosely bound cofactors in hydrolases, whereas heme acts as a prosthetic group in hemoglobin and cytochromes, permanently embedded to support oxygen transport or electron transfer.^[37] Terminological ambiguities have persisted in biochemical literature, particularly regarding coenzymes that exhibit varying binding affinities. In some cases, organic coenzymes like flavin adenine dinucleotide (FAD) are classified as prosthetic groups when they bind tightly and covalently in flavoproteins, such as succinate dehydrogenase, blurring the lines between transient coenzymes and permanent prosthetic groups. These inconsistencies stem from historical usage where the distinction depended on observed binding strength rather than a strict functional divide.^[38] From an evolutionary standpoint, prosthetic groups have enabled the development of specialized, efficient catalytic machinery within multi-subunit enzyme complexes, such as those in the respiratory chain. By providing stable, non-diffusible sites for redox reactions, they minimize intermediate loss and enhance overall metabolic flux, as evidenced in the modular evolution of complex II enzymes like succinate dehydrogenase, where prosthetic groups like FAD and iron-sulfur clusters integrate seamlessly across subunits.^[39]

Versus Apo- and Holoenzymes

Prosthetic groups are integral to the functional states of many proteins and enzymes, distinguishing between inactive and active forms. The protein component without its prosthetic group is termed the apoprotein (or apoenzyme in the case of enzymes), which typically lacks biological activity due to the absence of the essential non-protein moiety. For instance, in hemoglobin, the apoprotein globin cannot bind oxygen without its heme prosthetic group, rendering it incapable of oxygen transport.^[40] In contrast, the holoprotein (or holoenzyme) refers to the complete, functional unit comprising the apoprotein bound to its prosthetic group, which restores or enables full activity.^[41] This binary distinction highlights how prosthetic groups are not merely accessories but define the protein's operational capability. In laboratory settings, apoproteins are routinely isolated from holoproteins to study prosthetic group interactions and protein function. A common method involves extracting the prosthetic group, such as heme, using acid-acetone precipitation, which disrupts the heme-protein bonds without denaturing the apoprotein excessively.^[42] The resulting apoprotein can then be reconstituted with the prosthetic group to form the holoprotein, allowing researchers to investigate binding kinetics, structural changes, and functional restoration.^[43] This approach is particularly valuable for heme-containing proteins, where reconstitution confirms the prosthetic group's role in stabilizing the active conformation. Understanding the apo- and holo-states has significant implications for protein engineering and biomedical applications. In protein engineering, isolating apoproteins facilitates targeted modifications to the binding site or scaffold, enabling the design of novel holoproteins with altered redox properties or substrate specificities, as seen in engineered hemoproteins for biocatalysis.^[44] Clinically, disruptions in prosthetic group incorporation, such as heme deficiencies, lead to apo-like states in proteins, contributing to disorders like congenital sideroblastic anemias, where impaired heme biosynthesis causes ineffective erythropoiesis and anemia.^[45] These insights underscore the prosthetic group's pivotal role in transitioning proteins from inert to functional forms.

Biological Functions

Catalytic Roles

Prosthetic groups play a pivotal role in enzymatic catalysis by directly participating in the chemical transformations of substrates, often serving as transient carriers of reactive intermediates or electron equivalents within the active site. These tightly bound cofactors enable enzymes to achieve reaction rates far exceeding those of uncatalyzed processes, facilitating essential metabolic transformations through mechanisms such as redox shuttling, group transfer, and substrate activation.^[1] In redox catalysis, prosthetic groups like heme and flavin mononucleotide (FMN) mediate electron transfer between substrates and other cellular components. Heme, containing an iron center, facilitates one-electron transfers in enzymes such as cytochromes, where it cycles between Fe(III) and Fe(II) states to propagate electrons along the respiratory chain, and in cytochrome P450 monooxygenases, which use heme to activate molecular oxygen for substrate oxidation.^[46] Similarly, FMN acts as a redox mediator in flavoproteins, accepting and donating electrons via its isoalloxazine ring, which supports two-electron transfers critical for oxidative processes in various dehydrogenases and oxidases.^[47] A general representation of this process is:

\text{Oxidized prosthetic group} + \text{substrate (reduced)} \rightleftharpoons \text{Reduced prosthetic group} + \text{substrate (oxidized)}

This electron shuttling is fundamental to energy conservation in cellular respiration and photosynthesis, where prosthetic groups in complexes like cytochrome bc1 and b6f enable proton translocation and ATP synthesis.^[48] Prosthetic groups also catalyze group transfer reactions by temporarily binding and relocating functional moieties. For instance, biotin serves as a mobile carboxyl carrier in carboxylases, where it is first carboxylated at its ureido nitrogen using CO2 and ATP, then transfers the carboxyl group to acceptors like acetyl-CoA in fatty acid synthesis.^[49] In transaminases, pyridoxal phosphate (PLP) facilitates amino group transfer by forming a Schiff base with the substrate amino acid, enabling the exchange of the amino group with a keto group from an α-keto acid counterpart.^[50] In metalloenzymes, inorganic prosthetic groups such as Zn²⁺ directly activate substrates for hydrolysis or other reactions. In carbonic anhydrase, the Zn²⁺ ion coordinates a water molecule to generate a nucleophilic hydroxide that polarizes and attacks CO2, accelerating the hydration to bicarbonate by approximately 10⁶-fold compared to the uncatalyzed rate.^[51] These catalytic roles underscore the indispensability of prosthetic groups in core metabolic pathways, including respiration for ATP production and photosynthesis for carbon fixation.^[1]

Structural and Regulatory Roles

Prosthetic groups play crucial roles in maintaining the structural integrity of proteins beyond their catalytic functions. In hemoglobin, the heme prosthetic group stabilizes the native folding of globin subunits by facilitating the assembly of alpha-helical segments into the characteristic globin fold, which is essential for the protein's quaternary structure.^[52] Beyond structural support, prosthetic groups enable transport functions in non-enzymatic proteins. The heme group in myoglobin and hemoglobin reversibly binds oxygen, allowing these proteins to facilitate its transport from lungs to tissues while preventing oxidative damage through the hydrophobic environment provided by the globin chain.^[53] Prosthetic groups also serve as sensors in regulatory pathways. Heme acts as a regulatory prosthetic group in nitric oxide signaling by binding to the ferroheme in soluble guanylyl cyclase, triggering conformational changes that activate cyclic GMP production and vasodilation.^[54] In circadian rhythm regulation, heme binds to proteins like CLOCK and Rev-erbβ, modulating their interactions with DNA and influencing gene expression rhythms essential for metabolic homeostasis.^[55]^[56] In non-enzymatic proteins such as rhodopsin, the retinal prosthetic group undergoes light-induced isomerization from 11-cis to all-trans, driving conformational changes in the opsin protein that initiate visual signal transduction in photoreceptor cells.^[57] Disruptions in prosthetic group integration, particularly heme, are linked to diseases. Mutations in enzymes of the heme biosynthetic pathway cause porphyrias, leading to accumulation of toxic intermediates and clinical manifestations like acute neurovisceral attacks due to impaired heme incorporation into proteins.^[58]

Types and Examples

Organic Prosthetic Groups

Organic prosthetic groups are tightly bound, non-protein organic molecules that are essential components of many enzymes and proteins, often derived from vitamins and playing critical roles in catalysis. These groups are distinguished by their carbon-based structures, which enable specific chemical reactivities, and their covalent or very tight non-covalent attachments to the protein moiety. Unlike inorganic prosthetic groups, which typically involve metal ions or clusters, organic ones frequently originate from dietary vitamins or endogenous synthesis pathways in organisms.^[47] One of the most prominent organic prosthetic groups is heme, a tetrapyrrole macrocycle consisting of four pyrrole rings linked by methine bridges, with a central ferrous iron (Fe²⁺) atom coordinated to the nitrogen atoms of the pyrroles. Heme is covalently bound via thioether linkages in some proteins or non-covalently associated in others, and it is found in hemoglobin, where it enables oxygen binding and transport, as well as in cytochromes involved in electron transfer during respiration. The iron in heme can switch between Fe²⁺ and Fe³⁺ oxidation states, facilitating redox reactions.^[5] Flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) are riboflavin (vitamin B₂)-derived prosthetic groups characterized by an isoalloxazine ring system that undergoes reversible reduction and oxidation. FMN consists of the isoalloxazine ring linked to a phosphate group, while FAD features an additional adenosine diphosphate moiety; both are often covalently bound to enzymes via histidine or cysteine residues. These flavins serve as prosthetic groups in oxidoreductases, such as succinate dehydrogenase (which uses FAD) and NADH dehydrogenase (which incorporates FMN), enabling one- or two-electron transfer processes critical for metabolism. Approximately 75% of flavoproteins utilize FAD, with the remainder using FMN.^[59] Pyridoxal phosphate (PLP), the active form of vitamin B₆, features a pyridine ring with an aldehyde group at the 4' position and a phosphate ester at the 5' position, allowing it to form Schiff base intermediates with amino groups. PLP is typically bound through non-covalent interactions, including hydrogen bonding and hydrophobic contacts, in the active sites of enzymes. It acts as a prosthetic group in aminotransferases, such as alanine aminotransferase, where the aldehyde facilitates transamination reactions by stabilizing carbanion intermediates during amino acid metabolism. PLP-dependent enzymes account for over 140 reactions across organisms, primarily in amino acid pathways, with approximately 50 in humans.^[60] Biotin, also known as vitamin H, is a bicyclic heterocyclic compound with a ureido ring fused to a tetrahydrothiophene ring, attached to a valeric acid side chain. Biotin is covalently linked to a specific lysine residue on enzymes via an amide bond formed by biotin protein ligase, creating a flexible "swinging arm" for substrate shuttling. As a prosthetic group in carboxylases like acetyl-CoA carboxylase, biotin mediates CO₂ transfer during fatty acid synthesis and gluconeogenesis. The ureido ring's nitrogen atoms are key to its carboxylation by bicarbonate.^[61] Thiamine pyrophosphate (TPP), derived from vitamin B₁ (thiamine), comprises a thiazolium ring linked to a pyrimidine ring and a pyrophosphate group, with the thiazolium C2-H bond enabling nucleophilic carbanion formation. TPP is non-covalently but tightly bound in enzymes through interactions with the phosphate and heterocyclic rings. It functions as a prosthetic group in decarboxylases, such as pyruvate dehydrogenase, where it stabilizes enamine intermediates during α-keto acid decarboxylation in energy metabolism. TPP's role is conserved across species, reflecting its essentiality in carbohydrate catabolism.^[62] These organic prosthetic groups are predominantly vitamin derivatives, obtained through diet in animals or synthesized de novo in plants and microorganisms, underscoring their biochemical universality. Examples like heme, flavins, PLP, biotin, and TPP illustrate how organic structures provide versatile reactivity while remaining stably integrated into protein frameworks.

Inorganic Prosthetic Groups

Inorganic prosthetic groups consist of metal ions or clusters that are covalently or tightly bound to proteins, enabling essential functions such as electron transfer and catalysis through their unique coordination chemistry. These groups, often involving transition metals, are integral to the active sites of enzymes and are particularly prevalent in processes requiring redox activity or Lewis acid assistance. Unlike organic prosthetic groups, which rely on carbon-based frameworks, inorganic ones emphasize elemental metal centers and their ligands from protein residues like cysteine or histidine.^[63] Iron-sulfur ([Fe-S]) clusters represent a prominent class of inorganic prosthetic groups, featuring iron atoms bridged by sulfide ions and coordinated by cysteine residues. In ferredoxins, [2Fe-2S] clusters, typically ligated by four cysteines, facilitate low-potential electron transfer with reduction potentials ranging from -500 to -150 mV, supporting processes like photosynthesis and cofactor biosynthesis. Similarly, [4Fe-4S] clusters in ferredoxins and nitrogenases, coordinated by motifs such as Cys-X₂-Cys-X₂-Cys-Xₙ-Cys, enable electron shuttling from -650 to -250 mV, crucial for nitrogen fixation in anaerobic diazotrophs where electrons reduce N₂ to NH₃ via the enzyme's P-cluster. These clusters' cubane-like structures allow reversible Fe³⁺/Fe²⁺ redox cycling, underscoring their role in ancient metabolic pathways.^[64]^[63] The iron atom in heme serves as a key inorganic prosthetic component, embedded at the center of a porphyrin ring and coordinated by four nitrogen atoms from the porphyrin, with axial ligands often provided by protein histidines. This octahedral coordination enables the Fe²⁺/Fe³⁺ redox couple, facilitating oxygen binding in myoglobin and hemoglobin or electron transfer in cytochromes, where the metal's d-orbital overlap with ligands tunes reactivity. In hemoproteins, the central Fe coordination minimizes reorganization energy during redox events, enhancing efficiency in mitochondrial respiration.^[65] Zinc ions function as inorganic prosthetic groups in enzymes like alcohol dehydrogenase (ADH) and carbonic anhydrase (CA), adopting tetrahedral coordination geometries that polarize substrates. In ADH, the catalytic Zn²⁺ is bound by two cysteines, one histidine, and a water molecule, stabilizing the entatic state for hydride transfer during alcohol oxidation, while a structural Zn²⁺ with four cysteines maintains protein folding. In CA, Zn²⁺ coordinates three histidines (His94, His96, His119) and a solvent, acting as a Lewis acid to lower the pKₐ of bound water to ~7, generating nucleophilic hydroxide for CO₂ hydration to bicarbonate. This coordination enhances catalytic rates up to 10⁶ s⁻¹, vital for pH regulation and respiration.^[66]^[67] Copper centers in proteins exemplify inorganic prosthetic groups for redox chemistry, classified as type I (blue copper) or type II sites. Type I Cu in blue copper proteins like plastocyanin features a distorted tetrahedral geometry with two histidines, one cysteine, and one methionine, enabling rapid outer-sphere electron transfer with minimal structural change between Cu(I) and Cu(II) states (potentials ~+200 to +800 mV). Type II Cu in cytochrome c oxidase coordinates three histidines and a water/hydroxide, forming the Cu_B site that couples with heme a₃ for O₂ reduction to water, driving proton pumping in aerobic respiration. These sites' ligand fields optimize redox potentials for efficient electron flow.^[68] Molybdenum acts as an inorganic prosthetic group in xanthine oxidase, where it coordinates a hybrid molybdopterin cofactor via dithiolene sulfurs from the pterin ring, plus an oxo, sulfido, and hydroxo ligand in a distorted square-pyramidal geometry. This setup facilitates oxygen atom transfer, reducing Mo(VI) to Mo(IV) during purine hydroxylation (e.g., xanthine to urate), with electrons relayed through [Fe-S] clusters and FAD. The Mo-pterin hybrid enhances substrate specificity and catalytic turnover (~10 s⁻¹), essential for purine catabolism.^[69] These inorganic prosthetic groups predominantly enable Lewis acid catalysis—such as Zn²⁺ polarizing substrates—or redox reactions via variable oxidation states, with [Fe-S] clusters particularly abundant in anaerobic metabolism due to their evolutionary antiquity. For instance, [Fe-S]-dependent enzymes like nitrogenases and hydrogenases underpin ancient pathways in oxygen-free environments, facilitating electron transfer in microbial biogeochemical cycles such as nitrogen fixation and H₂ production. Their prevalence reflects an early geochemical role in prebiotic redox chemistry.^[63]

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This review presents a selection of engineered redox proteins achieved through these methods, resulting in a manipulation in redox potentials.
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Iron Metabolism in the Disorders of Heme Biosynthesis - PMC
Two disease groups, collectively known as porphyrias and congenital sideroblastic anemias, are both caused by an impairment in some steps of heme biosynthesis.
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Cytochromes P450: a success story - PMC - PubMed Central - NIH
In all P450s, heme is bound in a structurally conserved protein core, allowing them to catalyze regioselective and stereoselective oxidation of hydrocarbons.
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The Diverse Roles of Flavin Coenzymes - Nature's Most Versatile ...
Flavoenzymes, which contain FMN and/or FAD as prosthetic groups, catalyze many of the one- and two-electron oxidation/reduction reactions critical to the ...
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Amazing structure of respirasome: unveiling the secrets of cell ...
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Structure and function of biotin-dependent carboxylases - PMC
This review summarizes our current knowledge on the ... Chemical and catalytic mechanisms of carboxyl transfer reactions in biotin-dependent enzymes.
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Structural Consideration of the Working Mechanism of Fold Type I ...
Jul 23, 2019 · The transamination reaction occurs through two sequential half reactions via PLP: 1) the oxidative deamination of an amino group donor and 2) ...
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Structure and mechanism of carbonic anhydrase - PubMed
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Hemoglobin Variants: Biochemical Properties and Clinical Correlates
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Structure and calcium-binding studies of calmodulin-like domain of ...
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Hemoglobin: Structure, Function and Allostery - PMC
The heme consists of a ferrous ion held in the center of a porphyrin and coordinated by the four nitrogen atoms of the porphyrin ring. The Fe is also covalently ...
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The NO-heme signaling hypothesis - PubMed
Canonically, the NOS-derived NO diffuses through the (inter)cellular milieu to bind the prosthetic ferro(Fe2+)-heme group of the soluble guanylyl cyclase (sGC).
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Heme binding to human CLOCK affects interactions with the E-box
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The heme-regulatory motif of nuclear receptor Rev-erbβ is a key ...
Rev-erbβ is a heme-responsive transcription factor that regulates genes involved in circadian rhythm maintenance and metabolism, effectively bridging these ...
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Light-Induced Conformational Changes of Rhodopsin Probed ... - NIH
A novel fluorescence method has been developed for detecting the light-induced conformational changes of rhodopsin and for monitoring the interaction ...
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Heme biosynthesis and the porphyrias - PMC - NIH
In each specific porphyria the activity of specific enzymes in the heme biosynthetic pathway is defective and leads to accumulation of pathway intermediates.
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Pyridoxal 5'-Phosphate: Electrophilic Catalyst Extraordinaire - PMC
PLP is used as a cofactor in enzyme-catalyzed racemization and transamination (R1 = H), decarboxylation (R1 = CO2−) and retroaldol cleavage (R1 = CH2OH) ...
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The biotin enzyme family: conserved structural motifs and ... - PubMed
The biotin carboxylase family is comprised of a group of enzymes that utilize a covalently bound prosthetic group, biotin, as a cofactor ... Acyl-coenzyme ...
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Presence of thiamine pyrophosphate in mammalian peroxisomes
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Iron-sulfur protein odyssey: exploring their cluster functional ...
In this review, we will present three main functions of the Fe-S clusters and explain the difficulties encountered to identify Fe-S proteins.
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Iron-sulfur protein odyssey: exploring their cluster functional ...
May 14, 2024 · In this review, we will present three main functions of the Fe-S clusters and explain the difficulties encountered to identify Fe-S proteins.Missing: paper | Show results with:paper
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Heme: The Lord of the Iron Ring - PMC - PubMed Central
As such, heme is an essential molecule that is present in all cells, and functions as the prosthetic group for numerous hemoproteins such as hemoglobin, ...
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The role of zinc for alcohol dehydrogenase structure and function
Zinc plays an important role in the structure and function of many enzymes, including alcohol dehydrogenases (ADHs) of the MDR type (mediumchain dehydrogenases ...
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Elucidating the role of metal ions in carbonic anhydrase catalysis - NIH
Sep 11, 2020 · The active site zinc ion is tetrahedrally coordinated to the protein by the imidazole groups ... tetrahedral metal coordination. d Upon CO2 ...
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Redox processes in Cu-binding proteins: the “in-between” states in ...
Sep 13, 2023 · In most organisms, copper (Cu) represents an essential redox cofactor for electron-transfer proteins (e.g. plastocyanin, azurin) and enzymes, ...
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Chemical Nature and Reaction Mechanisms of the Molybdenum ...
The enzyme is a target of drugs for therapy of gout or hyperuricemia. We review the chemical nature and reaction mechanisms of the molybdenum cofactor of XOR, ...