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PubMed2025

A Sequence Motif Enables Widespread Use of Non-Canonical Redox Cofactors in Natural Enzymes.

Non-canonical redox cofactors (NRCs) are promising alternatives to nicotinamide adenine dinucleotide (phosphate) (NAD(P)+) for biomanufacturing due to low cost and exquisite electron delivery control, yet their adoption is limited by the scarcity of compatible enzymes. Here, we screened the aldehyde dehydrogenase (ALDH) protein family and identified a conserved RH/QxxR sequence motif that enables widespread NRC activity among natural enzymes. Bos taurus ALDH3a1 and Pseudanabaena biceps ALDH exhibit unprecedented turnover with nicotinamide mononucleotide (NMN+), with kcat values matching or exceeding that of NAD+ and surpassing most engineered NRC-active enzymes by 10 to 105-fold, based on the relative NRC to native activity. Structural and dynamic analyses reveal this motif reinforces cofactor positioning and pre-organizes the active site without dependence on the adenosine monophosphate moiety of NAD+. When introduced into diverse ALDH scaffolds, the RH/QxxR motif enhances NMN+ activity up to 60-fold. In addition to NMN+, this motif also supports activity across multiple non-nucleotide, simple synthetic NRCs such as 1-(2-carbamoylmethyl)nicotinamide (AmNA+). These findings elucidate Nature's solution to the engineering challenge of obtaining NRC-active enzymes and offers a blueprint to mine latent evolutionary plasticity in natural enzymes that serve as superior engineering starting points.

Active site pre-organization↗
PubMed1975

Nicotinamide adenine dinucleotide phosphate-specific glutamate dehydrogenase of Neurospora. III. Inactivation by nitration of a tyrosine residue involved in coenzyme binding.

Neurospora glutamate dehydrogenase (NADP-specific) is rapidly inactivated upon reaction with tetranitromethane. This inactivation is completely prevented by the presence of coenzyme (NADP) or nicotinamide mononucleotide (NMN) but not by substrate. NADH, or 2'-monophosphoadenosine-5'-diphosphoribose. Amino acid analysis indicates that the primary effect of modification is nitration of a single residue of tyrosine per polypeptide chain. We have identified the reactive tyrosine by isolation of a single, uniquely labeled peptide after hydrolysis with trypsin followed by cleavage with cyanogen bromide. The modified residue proved to be tyrosine-168 in the linear sequence. This residue is not present in the part of the sequence that had been previously implicated as involved in the binding of the adenylate portion of the coenzyme. Both NMN and 2-monophosphoadenosine-5'-diphosphoribose act as competitive inhibitors of NADP in the oxidation of glutamate with Ki values of 4.65 x 10(-4) M and 4.30 x 10(-4) M, respectively. Thus, the specific protection afforded by NADP and NMN, but not by 2'-monophosphoadenosine-5'-diphosphoribose, indicates that tyrosine-168 is involved in binding the nicotinamide portion of the coenzyme.

Amino Acid Sequence↗
PubMed1979

Age-related changes in catecholamine metabolites of human urine from birth to adulthood.

Catecholamines (dopamine [DA], norepinephrine [NE], epinephrine [E]), methoxyamines (3-methoxytyramine [MT], normetanephrine [NMN], metanephrine [MN]), DOPA, and acidic metabolites (3,4-dihydroxyphenylacetic acid [DOPAC], vanilmandelic acid [VMA]) were determined in human urines from one day of age to adulthood, in order to investigate sympatho-adrenal development during life. All adrenergic compounds are present in neonate urines on the first day of life, but their postnatal evolution is quite different according to the nature of metabolites. Daily E, MN and VMA amounts remain low until the 10th month of life; daily NE, MT and DOPA levels increase progressively, but, in contrast, NMN amounts are already high in the neonatal period and increase only beyond the fourth year of age. DA is at either age the predominant catecholamine but its elimination is relatively more important in the neonatal period.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1976

Effect of substrate pretreatment on renal organic ion transport in the adult rat.

The ability of renal cortical slices to accumulate PAH and NMN was not significantly affected by pretreatment of adult rats with large doses of PAH. Pretreatment of adult rats with THAM significantly increased PAH accumulation but had no effect on NMN. Inulin and PAH clearance and filtration fraction were significantly decreased by PAH pretreatment but unaffected by THAM pretreatment. The effects of pretreatment on transport are probably due to non-specific toxicity.

Aminohippuric Acids↗
PubMed1978

The influence of pH on the sex-related differences in renal organic ion transport.

The stimulating effects of elevated medium pH and androgen on in vitro transport of p-aminohippurate and N-methylnicotinamide (NMN) were additive, although the androgenic effect was pH-dependent only in the case of NMN. The similarity of response of the 2 systems supports the idea of a common passive efflux pathway for organic anions and cations.

Aminohippuric Acids↗
PubMed1975

Depression by NAD of x-ray-induced repair-type DNA synthesis in toluene-treated Bacillus subtilis.

NAD prevents a DNA repair-type synthesis that is dependent on polymerase I in toluene-treated, X-irradiated Bacillus subtilis. In unirradiated preparations, NAD had little effect on an ATP-dependent, semiconservative synthesis but partially inhibited a repair-type synthesis. In a mutant lacking polymerase I (polA1-), the presence of NAD did not affect dTTP utilization in DNA synthesis. Nicotinamide mononucleotide (NMN) partially reverses the NAD inhibition of repair-type DNA synthesis. NADP and FAD were ineffective as substitutes for NAD. Since NAD is the cofactor for polynucleotide ligase in Bacillus subtilis and NMN is known to discharge AMP from the active AMP ligase complex, it is proposed that activation of DNA ligase reduces dTMP incorporation by reducing sites for, or limiting DNA polymerase I action.

Adenosine Triphosphate↗
PubMed1976

The interaction of borate and sulfite with pyridine nucleotides.

The kinetics and equilibria of the borate interaction at ribose with NAD+ and NMN+ have been measured using as a chromophoric probe the perturbation effect borate has on the addition of sulfite to the 4 position of the nicotinamide ring. NAD+ and NMN+ have more favorable borate association constants than do their corresponding sulfite addition complexes. The rate of interaction of the ribose moiety with borate at low borate buffer concentration is dependent on the concentration of both borate and boric acid. At high borate concentration the rate becomes independent of borate concentration, indicating the existence of a two-step process for the interaction of NAD-sulfite with borate with a change of rate-determining step from the interaction of the ribose hydroxyl group with borate at low borate to an elimination of sulfite at high borate concentration. A linear free energy relationship with a slope of 0.94 describes an increased reactivity of the nucleotide for sulfite as the affinity of the nucleotide for sulfite increases.

Binding Sites↗
PubMed1976

Effects of substrate and inhibitor binding on thermal and proteolytic inactivation of rat liver transhydrogenase.

The thermostability and proteolytic inactivation of rat liver submitochondrial particle transhydrogenase was studied in the presence of pyridine dinucleotide substrates and a variety of divalent metal and nucleotide inhibitors. Relative to the unliganded enzyme, the NADPH-enzyme complex was more thermostable and showed a twofold greater rate of tryptic inactivation, while the NADP+-enzyme complex was more thermolabile and only slightly more susceptible to tryptic inactivation. Neither NAD+ nor NADH significantly affected thermostability or proteolysis. Similar effects of these ligands were observed for the non-energy-linked and energy-linked transhydrogenase reactions, indicating that both activities are catalyzed by the same enzyme. In thermal experiments, acetyl-CoA, 2'-AMP, and NMNH stabilized, palmitoyl-CoAlabilized, and dephospho-CoA, CoA, NMN+, and 5'-AMP had little effect on enzyme stability. Tryptic inactivation was inhibited by 2'-AMP and NMN+ but was not influenced by the other nucleotide inhibitors. Divalent metal ion inhibitors (Mg2+, Ca2+, Mn2+, Ba2+, and Sr2+) stabilized transhydrogenase against thermal inactivation and promoted tryptic inactivation.

Animals↗
PubMed2026

A sequence motif enables widespread use of noncanonical redox cofactors in natural enzymes.

Noncanonical redox cofactors (NRCs) are low-cost alternatives to the natural redox cofactors nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+) for biomanufacturing, offering exquisite electron-delivery control, yet their adoption is limited by the scarcity of compatible enzymes. Screening the aldehyde dehydrogenase (ALDH) family, we identified a conserved RH/QxxR motif that enables widespread NRC activity among natural enzymes. Bos taurus ALDH3a1 exhibits unprecedented turnover with nicotinamide mononucleotide (NMN+), with kcat values exceeding NAD+ and surpassing most engineered NRC-active enzymes by 10-105-fold. Structural analyses reveal that this motif reinforces cofactor positioning and preorganizes the active site independently of the NAD+ adenosine monophosphate moiety. This motif supports activity across simple-synthetic NRCs such as 1-(2-carbamoylmethyl)nicotinamide and, when introduced into diverse ALDH scaffolds, enhances NMN+ activity up to 60-fold. These findings elucidate nature's solution to engineering NRC-active enzymes and offer a blueprint to mine latent evolutionary plasticity in natural enzymes that serve as superior engineering starting points.

Journal Article↗
PubMed1977

Dinucleoside pyrophosphate are substrates for T4-induced RNA ligase.

RNA ligase isolated from bacteriophage T4-infected Escherichia coli will utilize a number of different compounds with the general structure Ado-5'PP-X as substrates in an ATP-independent reaction. The P-X portions of these molecules are transferred to the 3'-hydroxyl of an oligoribonucleotide to form a phosphodiester bond, and the Ado-5'P (AMP) portion is released. AMP, CMP, GMP, UMP, dTMP, NMN, alphaNMN, reduced NMN, FMN, Rib-5P, phosphopantetheine, and cyanoethylphosphate all have been added to [Cyd-3H](Ap)3C from their corresponding AMP adducts. Contrary to the relative lack of specificity of RNA ligase for the P-X -group added, the failure of NADP+, deamino-NAD+, epsilonNCD+, epsilon NAD and CoA to react indicates that the enzyme shows a high degree of selectivity for the AMP portion of the substrate. The diversity of chemical groups that can be efficiently added suggests that this reaction of RNA ligase will prove useful for the modification of the 3' ends of RNA molecules.

Coliphages↗
PubMed1975

Renal transport of organic acids and bases in genetically obese mice.

Accumulation of p-aminohippurate (PAH) and N-methylnicotinamide (NMN) by renal cortical slices was used to estimate transport capacity for organic anions and cations, respectively. In a previous study, renal organic anion transport appeared to be selectively depressed in animals rendered obese by high fat feeding. However, the effects of obesity could not be discretely separated from the effects of the 30% fat diet used to produce the obesity. Genetically obese hyperglycemic mice provided a model to determine the effect of obesity on renal transport systems without the complication due to diet. Accumulation of both PAH and NMN was depressed in renal cortical slices from genetically obese mice. Addition of plasma from thin or obese animals increased PAH accumulation by slices from thin animals. Accumulation by slices from obese animals was unaffected by addition of plasma. Oxygen consumption with acetate in the medium was less in kidneys from obese mice than kidneys from thin mice. Thus, in addition to inhibition of transport capacity, renal cortex of genetically obese mice has a biochemical defect that prevents response to stimulators. It is concluded that several renal functions are depressed in the genetically obese hyperglycemic mouse. Whether the depressed function results from the obesity or is concomitant with the gene for obesity is as yet undertermined.

Acetates↗
PubMed1979

Metabolic adrenergic changes during submaximal exercise and in the recovery period in man.

The urinary excretion of dihydroxyphenylalanine (DOPA), catecholamines (CA) [dopamine (DA), norepinephrine (NE), and epinephrine (e)], their 3-O-methylated derivatives [3-O-methyldopamine (3-MT), normetanephrine (NMN), and metanephrine (MN)], and their deaminated metabolites [dihydroxyphenylacetic acid (DOPAC) and vanilmandelic acid (VMA)] was studied in six healthy men, at rest during short-term (15 min) or exhaustive submaximal exercise, and in the 2-h postexercise recovery period. During short-term exercise only NE and VMA excretions increased, whereas in postexercise period only DA output was enhanced. Exhaustive muscular work induced a rise in NE and E excretion during the test, and an increase in DA, NE, and NMN urinary levels during postexercise recovery, while the output of deaminated metabolites was unaltered. It is concluded that both release and synthesis of CA are stimulated by submaximal exercise, which induces, in addition to NE, a specific release of DA. A possible role of NE in lipid mobilization during recovery from exhaustive muscular work is evoked. The origin and role of released DA are also discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1978

[Effect of submaximal muscular exercise of short duration on urinary excretion of catecholamines, DOPA and their metabolites].

Thirteen human subjects were submitted to a moderate muscular work on ergometric bicycle (at intensity corresponding to 80% of maximal oxygen uptake during 10 min). No modifications were observed in the urinary amounts of the three catecholamines (A, NA, DA), DOPA, DOPAC and 3-MT. On the contrary, the excretion of metadrenaline (MN) and normetadrenaline (NMN) was slightly increased, showing a mild stimulation of adrenergic system. Our result point out the interest of urinary methoxyamines as useful index of adrenergic activity in man. For experimental and physiopathological use, the metabolic alteration induced by a short submaximal muscular work is negligible for most adrenergic compounds, except for MN and NMN, the amounts of which are slightly modified.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Human erythrocyte glucose 6-phosphate dehydrogenase. Influence of coenzyme derivatives on thermostability and kinetic properties.

A number of derivatives of NADP(H) were tested with respect to their effectiveness in interacting with tetrameric glucose 6-phosphate dehydrogenase (G6PD) retaining only the fraction of "structural" coenzyme (4 moles NADP). Interaction was probed by two parameters: a) increased thermostability of G6PD activity, measured as the difference in the corresponding transition temperature (Tm) of samples containing and lacking the NADP derivatives, respectively; b) competitive inhibition toward NADP, expressed a Ki values. Protection afforded by the various effectors against thermal denaturation decreased in the following order: NADPH, NADP, PADP-ribose, adenosine 2',5'-P2. Other NADP derivatives, including 2',3' cyclic NADP, NMN, NMNH, nicotinamide, adenosine 2'-P, were uneffective in respect to this property. The kinetically measured affinity was the greatest for NADPH and decreased progressively for the following effectors: PADP-ribose, NADP, NMNH, PADP-glycolaldehyde, adenosine 2',5'-P2, PADP-ribitol, adenosine 2'-P. Nicotinamide and NMN were uneffective on NADP binding. These data show that the adenosine moiety of NADP is more critically involved than the nicotinamide portion in the interaction with human G6PD.

Drug Stability↗
PubMed1979

A functional arginine residue in NADPH-dependent aldehyde reductase from pig kidney.

Pig kidney aldehyde reductase is inactivated by 2,3-butanedione, phenylglyoxal, methylglyoxal, and 1,2-cyclohexanedione. 2,3-Butanedione caused the most rapid loss in enzyme activity, the rate of loss being proportional to the concentration of 2,3-butanedione. Neither D-glyceraldehyde nor pyridine 3-aldehyde, both substrates for this broadly specific enzyme, protected the enzyme from inactivation but 1 mM NADPH or NADP completely prevented the loss of activity by 2,3-butanedione suggesting the involvement of arginine in the binding of cofactor. Nicotinamide mononucleotide (NMN) (reduced form) offered no protection to inactivation whereas ADP-ribose phosphate gave complete protection indicating that it is the latter portion of NADPH which interacts with the essential arginine. Both NMN and ADP-ribose phosphate are competitive inhibitors of aldehyde reductase with respect to NADPH. Butanedione-modified aldehyde reductase could still bind to a blue dextran-Sepharose 4B column suggesting that the modified arginine did not bind NADPH. This was confirmed by fluorescence spectra which showed that chemically modified aldehyde reductase caused the same blue shift of NADPH fluorescence as did native aldehyde reductase. Of additional interest was the quenching of NADPH fluorescence by aldehyde reductase which, with one exception, is in contrast to the fluorescence behavior of all other oxidoreductases.

Aldehyde Oxidoreductases↗
PubMed1979

Renal excretion of pseudoephedrine in the rat.

Pseudoephedrine is an organic base used in the treatment of upper respiratory tract disorders. Surgical techniques and experimental procedures were developed to study the renal elimination mechanisms for this drug in the rat. The ability to measure renal clearance accurately and to demonstrate renal secretion by a carrier-mediated transport system was verified by comparing results from N'-methylnicotinamide (NMN) excretion studies with literature results. Renal tubular secretion of NMN was shown to be saturable and was inhibited by mepiperphenidol to the same extent as that reported in the literature. Pseudoephedrine was cleared by the kidney at a rate in excess of inulin and close to or possibly greater than renal plasma flow. In addition to filtration and secretion, pseudoephedrine appeared to be subject to pH dependent passive reabsorption. When the secretion of pseudoephedrine was studied in detail, it was found to be nonsaturable for plasma levels of pseudoephedrine ranging from 0.16 to 1.5 microgram/ml. Secretion, however, was inhibited by mepiperphenidol suggesting a carrier-mediated process.

Animals↗
PubMedDate not supplied

[Properties of NAD-pyrophosphorylase of the nuclei of liver cells of chickens].

Certain characteristics of chicken liver cells nuclei NAD-pyrophosphorylase (NMN-adenylytranspherase, EC 2.7.7.1) were investigated. It was established that NAD-pyrophosphorylase activity optimum pH is within interval of 7.0-7.5; temperature optimum - 38-39 degrees C; factor Q10 is equal to 2. Enzyme activation energy, inactivation energy and enthalpy were calculated; apparent Km values of NAD-pyrophosphorylase with respect to NMN and ATP are equal to 1.62-10(-7) M and 2.61-10(-7) M, respectively.

Adenosine Triphosphate↗
PubMed1978

Toward a biochemical classification of depressive disorders. II. Application of multivariate discriminant function analysis to data on urinary catecholamines and metabolites.

The previous article in this series reported on the differences in urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) in patients with various clinically defined subtypes of depressive disorders. We now report that further biochemical discrimination among depressive subtypes is provided by the following equation, derived empirically by applying multivariate discriminant function analysis to data on urinary catecholamine metabolits: Depression-type (D-type) score = C1(MHPG) + C2(VMA) + C3(NE) +C4(NMN + MN)/VMA + C0. In the original derivation of this equation, low scores were related to bipolar manic-depressive depressions, and high scores were related to unipolar nonendogenous (chronic characterological) depressions. Findings from a series of depressed patients whose biochemical data had not been used to derive this equation confirmed these differences in D-type scores among subtypes of depressions. The findings presented in this report further suggest that we can discriminate three biochemically discrete subgroups of depressive disorders.

Adult↗