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1.
Hjelmqvist L Norin A El-Ahmad M Griffiths W Jörnvall H 《Cellular and molecular life sciences : CMLS》2003,60(9):2009-2016
Alcohol dehydrogenases (ADHs) of the MDR type (medium-chain dehydrogenases/reductases) have diverged into two evolutionary groups in eukaryotes: a set of 'constant' enzymes (class III) typical of basal enzymes, and a set of 'variable' enzymes (remaining classes) suggesting 'evolving' forms. The variable set has larger overall variability, different segment variability, and variability also in functional segments. Using a major aldehyde dehydrogenase (ALDH) from cod liver and fish ALDHs deduced from the draft genome sequence of Fugu rubripes (Japanese puffer fish), we found that ALDHs form more complex patterns than the ADHs. Nevertheless, ALDHs also group into 'constant' and 'variable' sets, have separate segment variabilities, and distinct functions. Betaine ALDH (class 9 ALDH) is 'constant,' has three segments of variability, all non-functional, and a limited fish/human divergence, reminiscent of the ADH class III pattern. Enzymatic properties of fish betaine ALDH were also determined. Although all ALDH patterns are still not known, overall patterns are related to those of ADH, and group separations may be distinguished. The results can be interpreted functionally, support ALDH isozyme distinctions, and assign properties to the multiplicities of the ADH and ALDH enzymes. 相似文献
2.
B. Persson J. Hedlund H. Jörnvall 《Cellular and molecular life sciences : CMLS》2008,65(24):3879-3894
The MDR superfamily with ~350-residue subunits contains the classical liver alcohol dehydrogenase (ADH), quinone reductase,
leukotriene B4 dehydrogenase and many more forms. ADH is a dimeric zinc metalloprotein and occurs as five different classes
in humans, resulting from gene duplications during vertebrate evolution, the first one traced to ~500 MYA (million years ago)
from an ancestral formaldehyde dehydrogenase line. Like many duplications at that time, it correlates with enzymogenesis of
new activities, contributing to conditions for emergence of vertebrate land life from osseous fish. The speed of changes correlates
with function, as do differential evolutionary patterns in separate segments. Subsequent recognitions now define at least
40 human MDR members in the Uniprot database (corresponding to 25 genes when excluding close homologues), and in all species
at least 10888 entries. Overall, variability is large, but like for many dehydrogenases, subdivided into constant and variable
forms, corresponding to household and emerging enzyme activities, respectively. This review covers basic facts and describes
eight large MDR families and nine smaller families. Combined, they have specific substrates in metabolic pathways, some with
wide substrate specificity, and several with little known functions. 相似文献
3.
Norin A Piersma SR Duine JA Jörnvall H 《Cellular and molecular life sciences : CMLS》2003,60(5):999-1006
The primary structure of nicotinoprotein alcohol dehydrogenase (ADH) from Amycolatopsis methanolica was determined and used for modelling against known ADH structures, and for evaluation of the coenzyme binding. The results establish the medium-chain dehydrogenase/reductase nature of the nicotinoprotein ADH. Its subunit model and that of the human class Ibeta ADH subunit structure are similar, with mean a carbon deviations of 0.95 A, but they differ in seven loops. Nicotinoprotein ADH occupies a phylogenetic position intermediate between the dimeric and tetrameric ADH families. Two of the differing loops are important for coenzyme binding in the nicotinoprotein model, where one (with a Thr271Arg exchange towards the traditional enzyme) may suggest a slight rotation of the coenzyme adenine ring in the nicotinoprotein, and the other, with an Asn288 insertion, may suggest an extra hydrogen bond to its nicotinamide ribose, favouring stronger binding of the coenzyme. Combined with previous data, this suggests differences in the details of the tight coenzyme binding in different nicotinoproteins, but a common mode for this binding by loop differences. 相似文献
4.
Zinc plays an important role in the structure and function of many enzymes, including alcohol dehydrogenases (ADHs) of the
MDR type (mediumchain dehydrogenases/reductases). Active site zinc participates in catalytic events, and structural site zinc
maintains structural stability. MDR-types of ADHs have both of these zinc sites but with some variation in ligands and spacing.
The catalytic zinc sites involve three residues with different spacings from two separate protein segments, while the structural
zinc sites involve four residues and cover a local segment of the protein chain (Cys97-Cys111 in horse liver class I ADH).
This review summarizes properties of both ADH zinc sites, and relates them to zinc sites of proteins in general. In addition,
it highlights a separate study of zinc binding peptide variants of the horse liver ADH structural zinc site. The results show
that zinc coordination of the free peptide differs markedly from that of the enzyme (one His / three Cys versus four Cys),
suggesting that the protein zinc site is in an energetically strained conformation relative to that of the peptide. This finding
is a characteristic of an entatic state, implying a functional nature for this zinc site. 相似文献
5.
Hellgren M Strömberg P Gallego O Martras S Farrés J Persson B Parés X Höög JO 《Cellular and molecular life sciences : CMLS》2007,64(4):498-505
The metabolism of all-trans- and 9-cis-retinol/ retinaldehyde has been investigated with focus on the activities of human, mouse and rat alcohol dehydrogenase 2
(ADH2), an intriguing enzyme with apparently different functions in human and rodents. Kinetic constants were determined with
an HPLC method and a structural approach was implemented by in silico substrate dockings. For human ADH2, the determined Km values ranged from 0.05 to 0.3 μM and kcat values from 2.3 to 17.6 min−1, while the catalytic efficiency for 9-cis-retinol showed the highest value for any substrate. In contrast, poor activities
were detected for the rodent enzymes. A mouse ADH2 mutant (ADH2Pro47His) was studied that resembles the human ADH2 setup.
This mutation increased the retinoid activity up to 100-fold. The Km values of human ADH2 are the lowest among all known human retinol dehydrogenases, which clearly support a role in hepatic
retinol oxidation at physiological concentrations.
Received 12 October 2006; received after revision 6 December 2006; accepted 8 January 2007 相似文献
6.
Summary Three anti-horse liver alcohol dehydrogenase (HLADH) monoclonal antibodies are described. Two are specific for ADH and cross-react with class I and II enzymes from mouse, horse and Chinese hamster. They are specific for the native enzyme but do not inhibit enzyme activity except when combined at high concentration. The third antibody was isolated as a response to rabbit metallothionein. It binds metalloproteins and inhibits ADH activity. 相似文献
7.
Three anti-horse liver alcohol dehydrogenase (HLADH) monoclonal antibodies are described. Two are specific for ADH and cross-react with class I and II enzymes from mouse, horse and Chinese hamster. They are specific for the native enzyme but do not inhibit enzyme activity except when combined at high concentration. The third antibody was isolated as a response to rabbit metallothionein. It binds metalloproteins and inhibits ADH activity. 相似文献
8.
Hirschberg D Cederlund E Crosas B Jonsson A Tryggvason S Farrés J Parés X Bergman T Jörnvall H 《Cellular and molecular life sciences : CMLS》2001,58(9):1323-1326
A recent finding of a novel class of retinol-active alcohol dehydrogenase (ADH) in frog prompted analysis of this activity in other vertebrate forms. Surprisingly, yet another and still more unrelated ADH was identified in chicken tissues. It was found to be a member of the aldo-keto reductase (AKR) enzyme family, not previously known as an ADH in vertebrates. Its terminal blocking group and the N-terminal segment, not assigned by protein and cDNA structure analysis, were determined by electrospray tandem mass spectrometry after protein isolation by two-dimensional gel electrophoresis. The N terminus is Acetyl-Ala- and the N-terminal segment contains two consecutive Asn residues. The results establish the new ADH enzyme of the AKR family and show the usefulness of combined gel separation and mass spectrometry in enzyme-characterization. 相似文献
9.
Linder JU 《Cellular and molecular life sciences : CMLS》2006,63(15):1736-1751
Class III adenylyl cyclases are the most abundant type of cyclic AMP-producing enzymes. The adjustment of the cellular levels
of this second messenger is achieved by a variety of regulatory mechanisms which couple signals to adenylyl cyclase activity.
Because of the divergent nature of stimuli which impinge on these enzymes, highly individualized class III adenylyl cyclases
have evolved in metazoans, eukaryotic unicells and bacteria. Regulation usually exploits the dimeric structure of the catalyst,
whose active centres form at the dimer interface. The fold of the catalytic domains and the basic catalytic mechanisms are
similar in all class III adenylyl cyclases, and substrate binding generally closes the active site by an induced-fit mechanism.
Regulatory inputs can result in dramatic rearrangements of the catalytic domains within the dimer, which often are based on
rotational movements.
Received 13 February 2006; received after revision 16 March 2006; accepted 20 April 2006 相似文献
10.
Strömberg P Svensson S Hedberg JJ Nordling E Höög JO 《Cellular and molecular life sciences : CMLS》2002,59(3):552-559
The human alcohol dehydrogenase system is comprised of multiple forms that catalyse the oxidation/reduction of a large variety of alcohols and aldehydes. A transition that results in an Ile308Val substitution was identified in the human ADH2 gene by single-strand conformation polymorphism analysis. Screening a Swedish population revealed that Val308 was the most frequent allele (73%), and site-directed mutagenesis was used to obtain both allelozymes, which were expressed in Escherichia coli for characterisation. Thermostability was assayed by activity measurements and circular dichroism spectroscopy. The results showed that the 308Val substitution decreases protein stability, as compared to the Ile308 variant, an effect also demonstrated during prolonged storage. Ethanol, octanol, 12-hydroxydodecanoic acid and all-trans retinol were used as model substrates and, generally, slightly higher Km values were observed with Val at position 308. Finally, homology modelling, from mouse ADH2, further supported the decreased stability of the Val308 variant and located position 308 in the subunit interface of the molecule and in the vicinity of the active-site pocket entrance. In conclusion, the Ile308Val substitution represents a novel functional polymorphism within the human alcohol dehydrogenase gene cluster that may affect the metabolism of ethanol and other substrates. 相似文献
11.
R. Ladenstein J.-O. Winberg J. Benach 《Cellular and molecular life sciences : CMLS》2008,65(24):3918-3935
The structure-function relationships of alcohol dehydrogenases from the large family of short-chain dehydrogenase/reductase
(SDR) enzymes are described. It seems that while mammals evolved with a medium-chain alcohol dehydrogenase family (MDR), fruit
flies utilized an ancestral SDR enzyme. They have modified its function into an efficient alcohol dehydrogenase to aid them
in colonizing the emerging ecological niches that appeared around 65 million years ago. To the scientific community, Drosophila has now served as a model organism for quite some time, and Drosophila alcohol dehydrogenase is one of the best-studied members of the SDR family. The availability of a number of high-resolution
structures, accurate and thorough kinetic work, and careful theoretical calculations have enabled an understanding of the
structure-function relationships of this metal-free alcohol dehydrogenase. In addition, these studies have given rise to various
hypotheses about the mechanism of action of this enzyme and contribute to the detailed knowledge of the large superfamily
of SDR enzymes. 相似文献
12.
F. Leibenguth 《Cellular and molecular life sciences : CMLS》1977,33(11):1434-1436
Summary The relative band staining intensities of ADH isoenzymes in wheat and triticale suggest alloploid genome interactions. Rye ADH is scarcely affected by anti-wheat-ADH. Despite the evolutionary divergence of their Adh genes, ADH monomers of wheat and rye form enzymatically active heterodimers in triticale.Dedicated to Prof. Dr V. Schwartz, Tübingen, on the occasion of his 70th birthday.I thank Miss Hiltrud Wambach and Miss Rita Lippert for technical assistance. 相似文献
13.
The protozoan Crithidia fasciculata contains two different ribonuclease H activities. These enzymes display similar physical and biochemical characteristics to their homologues in higher eukaryotes, for instance calf thymus class I and class II ribonuclease H. Class I ribonuclease H of lower and higher eukaryotes can be activated by Mg2(+)- and Mn2(+)-ions. However, the presence of Mn2(+)-ions is inhibitory for the Mg2(+)-dependent class II ribonuclease H activity of Crithidia fasciculata and calf thymus. The protozoan class I-homologue enzyme appears to be serologically related to the class I ribonuclease H of calf thymus. 相似文献
14.
Dopamine beta-hydroxylase (DBH) enzyme activity was associated in rat superior cervical ganglion with tetrameric DBH-A (294,000 D) and dimeric DBH-B (147,000 D) and in rat adrenal gland with DBH-A and a novel molecular form of DBH, defined as DBH-C, with a molecular weight of 125,000 D. Pretreatment of the rats with cycloheximide markedly reduced DBH activity without altering the molecular heterogeneity. 相似文献
15.
Sergio Porté Agrin Moeini Irene Reche Naeem Shafqat Udo Oppermann Jaume Farrés Xavier Parés 《Cellular and molecular life sciences : CMLS》2011,68(6):1065-1077
Human ζ-crystallin is a Zn2+-lacking medium-chain dehydrogenase/reductase (MDR) included in the quinone oxidoreductase (QOR) family because of its activity
with quinones. In the present work a novel enzymatic activity was characterized: the double bond α,β-hydrogenation of medium-chain
2-alkenals and 3-alkenones. The enzyme is especially active with lipid peroxidation products such as 4-hydroxyhexenal, and
a role in their detoxification is discussed. This specificity is novel in the QOR family, and it is similar to that described
in the distantly related alkenal/one reductase family. Moreover, we report the X-ray structure of ζ-crystallin, which represents
the first structure solved for a tetrameric Zn2+-lacking MDR, and which allowed the identification of the active-site lining residues. Docking simulations suggest a role
for Tyr53 and Tyr59 in catalysis. The kinetics of Tyr53Phe and Tyr59Phe mutants support the implication of Tyr53 in binding/catalysis
of alkenal/one substrates, while Tyr59 is involved in the recognition of 4-OH-alkenals. 相似文献
16.
17.
N. H. Fraeyman E. J. Van de Velde F. H. De Smet 《Cellular and molecular life sciences : CMLS》1988,44(9):746-749
Summary Dopamine beta-hydroxylase (DBH) enzyme activity was associated in rat superior cervical ganglion with tetrameric DBH-A (294,000 D) and dimeric DBH-B (147,000 D) and in rat adrenal gland with DBH-A and a novel molecular form of DBH, defined as DBH-C, with a molecular weight of 125,000 D. Pretreatment of the rats with cycloheximide markedly reduced DBH activity without altering the molecular heterogeneity. 相似文献
18.
Summary The protozoanCrithidia fasciculata contains two different ribonuclease H activities. These enzymes display similar physical and biochemical characteristics to their homologues in higher eukaryotes, for instance calf thymus class I and class II ribonuclease H. Class I ribonuclease H of lower and higher eukaryotes can be activated by Mg2+- and Mn2+- ions. However, the presence of Mn2+-ions is inhibitory for the Mg2+-dependent class II ribonuclease H activity ofCrithidia fasciculata and calf thymus. The protozoan class I-homologue enzyme appears to be serologically related to the class I ribonuclease H of calf thymus. 相似文献
19.
Qian Han Tao Cai Danilo A. Tagle Jianyong Li 《Cellular and molecular life sciences : CMLS》2010,67(3):353-368
Kynurenine aminotransferases (KATs) catalyze the synthesis of kynurenic acid (KYNA), an endogenous antagonist of N-methyl-d-aspartate and alpha 7-nicotinic acetylcholine receptors. Abnormal KYNA levels in human brains are implicated in the pathophysiology
of schizophrenia, Alzheimer’s disease, and other neurological disorders. Four KATs have been reported in mammalian brains,
KAT I/glutamine transaminase K/cysteine conjugate beta-lyase 1, KAT II/aminoadipate aminotransferase, KAT III/cysteine conjugate
beta-lyase 2, and KAT IV/glutamic-oxaloacetic transaminase 2/mitochondrial aspartate aminotransferase. KAT II has a striking
tertiary structure in N-terminal part and forms a new subgroup in fold type I aminotransferases, which has been classified
as subgroup Iε. Knowledge regarding KATs is vast and complex; therefore, this review is focused on recent important progress
of their gene characterization, physiological and biochemical function, and structural properties. The biochemical differences
of four KATs, specific enzyme activity assays, and the structural insights into the mechanism of catalysis and inhibition
of these enzymes are discussed. 相似文献
20.
Mishra R Olofsson L Karlsson M Carlsson U Nicholls IA Hammarström P 《Cellular and molecular life sciences : CMLS》2008,65(5):827-839
The basis for the stability of thermophilic proteins is of fundamental interest for extremophile biology. We investigated
the folding and unfolding processes of the homotetrameric Thermoanaerobacter brockii alcohol dehydrogenase (TBADH). TBADH subunits were 4.8 kcal/mol less stable towards guanidinium chloride (GdmCl) unfolding
compared to urea, indicating ionic modulation of TBADH stability. Strongly denaturing conditions promoted mono-exponential
unfolding kinetics with linear dependence on denaturant concentration. Here TBADH unfolded >40-fold slower when extrapolated
from urea as compared to GdmCl unfolding. A marked unfolding hysteresis was shown when comparing refolding and unfolding in
urea. An unusual biphasic unfolding trajectory with an exceptionally slow phase at intermediate concentrations of GdmCl and
urea was also observed. We advocate that TBADH forms two distinctly different tetrameric isoforms, and likely an ensemble
of native states. This unusual supramolecular folding behavior has been shown responsible for formation of amyloidotic yeast
prion strains and can have functional importance for TBADH.
Received 9 November 2007; received after revision 19 December 2007; accepted 8 January 2008 相似文献