Properties of Sorbitol Dehydrogenase and Characterization of a Reactive Cysteine Residue Reveal Unexpected Similarities to Alcohol Dehydrogenases

Jeffery, Jonathan; Cummins, Laura; Carlquist, Mats; Jörnvall, Hans

doi:10.1111/j.1432-1033.1981.tb05693.x

Cited by 55 publications

(23 citation statements)

References 38 publications

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“…Consequently, it appears likely that sorbitol dehydrogenase lacks the second zinc atom. This conclusion agrees with zinc analyses of sorbitol dehydrogenase, which reveal the presence of only one zinc atom per subunit [28], compatible with the active-site zinc atom required for activity [2]. The second zinc atom in alcohol dehydrogenase and the surrounding protein region have not been ascribed any specific function [lo], so their probable absence from sorbitol dehydrogenase is not inconsistent with the basic similarities noted above.…”

Section: Interpretations Of Differences: Distant Relationship and Spesupporting

confidence: 77%

“…Alcohol dehydrogenases and polyol dehydrogenases show few substrate overlaps [2]. Consequently, the substrate binding sites must differ.…”

Section: Interpretations Of Differences: Distant Relationship and Spementioning

confidence: 99%

“…The complete primary structure of a sorbitol dehydrogenase is available [l]: the 354-residue subunit of the tetrameric [2] enzyme from sheep liver. This structure is now compared with those of yeast and horse liver alcohol dehydrogenases.…”

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confidence: 99%

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Extensive variations and basic features in the alcohol dehydrogenase – sorbitol dehydrogenase family

Jörnvall

Bahr‐Lindström

Jeffery

1984

European Journal of Biochemistry

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Structural comparisons of sorbitol dehydrogenase with zinc-containing 'long' alcohol dehydrogenases reveal distant but clear relationships. An alignment suggests 93 positional identities with horse liver alcohol dehydrogenase (25 % of 374 positions) and 73 identities with yeast alcohol dehydrogenase (20 %). Sorbitol dehydrogenase forms a link between these distantly related alcohol dehydrogenases and is in some regions more similar to one of them that they are to each other. 43 residues (1 1 %) are common to all three enzymes and include a heavy over-representation of glycine (half of all glycine residues in sorbitol dehydrogenase), showing the importance of space restrictions in protein structures.Four regions are well conserved, two in each domain of horse liver alcohol dehydrogenase. They are two segments close to the active-site zinc atom of the catalytic domain, and two in the central P-pleated sheet strands of the coenzyme-binding domain. These similarities demonstrate the general importance of internal and central building units in proteins.Large variations affect a region adjacent to the third protein ligand to the active-site zinc atom in horse liver alcohol dehydrogenase. Such changes at active sites of related enzymes are unusual. Other large differences concern the segment around the non-catalytic zinc atom of horse liver alcohol dehydrogenase; three of its four cysteine ligands are absent from sorbitol dehydrogenase. Three segments with several exchanges correspond to a continuous region with superficial areas, inter-domain contacts and inter-subunit interactions in the catalytic domain of alcohol dehydrogenase. They may correlate with the altered quaternary structure of sorbitol dehydrogenase. Regions corresponding to top and bottom P-strands in the coenzyme-binding domain of the alcohol dehydrogenase are also little conserved. Within sorbitol dehydrogenase, a large segment shows an internal similarity.The two distantly related alcohol dehydrogenases and sorbitol dehydrogenase form a triplet of enzymes illustrating basic protein relationships. They are ancestrally close enough to establish similarities, yet sufficiently divergent to illustrate changes in all but fundamental properties.The complete primary structure of a sorbitol dehydrogenase is available [l]: the 354-residue subunit of the tetrameric [2] enzyme from sheep liver. This structure is now compared with those of yeast and horse liver alcohol dehydrogenases. These three enzymes, known to have some structural similarities [2-41 suggesting evolutionary connections [3], are functionally related and participate in a common metabolic pathway from glucose [5]. The alcohol dehydrogenases show considerable divergence in primary structure, quaternary structure, isozyme development, substrate specificity and other functional characteristics [6-91, so detailed comparisons covering the entire structure of sorbitol dehydrogenase are necessary. Of particular interest are functionally important residues and adjacent regions, structures concerned with s...

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Section: Interpretations Of Differences: Distant Relationship and Spesupporting

confidence: 77%

“…Alcohol dehydrogenases and polyol dehydrogenases show few substrate overlaps [2]. Consequently, the substrate binding sites must differ.…”

Section: Interpretations Of Differences: Distant Relationship and Spementioning

confidence: 99%

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Extensive variations and basic features in the alcohol dehydrogenase – sorbitol dehydrogenase family

Jörnvall

Bahr‐Lindström

Jeffery

1984

European Journal of Biochemistry

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“…Mammalian SDH is a tetramer of four identical subunits with an overall molecular mass of 152 kDa and one catalytic zinc atom per subunit (11,15,16). The reconstitution of apo-SDH with free zinc ions is very fast and reaches 100% within 3 min (Fig.…”

Section: Kinetic Studies Of the Reconstitution Of Apo-sdh With Zincmentioning

confidence: 99%

The glutathione redox couple modulates zinc transfer from metallothionein to zinc-depleted sorbitol dehydrogenase

Jiang

Maret

Vallée

1998

Proc. Natl. Acad. Sci. U.S.A.

284

207

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The release and transfer of zinc from metallothionein (MT) to zinc-depleted sorbitol dehydrogenase (EC 1.1.1.14) in vitro has been used to explore the role of MT in cellular zinc distribution. A 1:1 molar ratio of MT to sorbitol dehydrogenase is required for full reactivation, indicating that only one of the seven zinc atoms of MT is transferred in this process. Reduced glutathione (GSH) and glutathione disulfide (GSSG) are critical modulators of both the rate of zinc transfer and the ultimate number of zinc atoms transferred. GSSG increases the rate of zinc transfer 3-fold, and its concentration is the major determinant for efficient zinc transfer. GSH has a dual function. In the absence of GSSG, it inhibits zinc transfer from MT, indicating that MT is in a latent state under the relatively high cellular concentrations of GSH. In addition, it primes MT for the reaction with GSSG by enhancing the rate of zinc transfer 10-fold and by increasing the number of zinc atoms transferred to four.65 Znlabeling experiments confirm the release of one zinc from MT in the absence of glutathione and the more effective release of zinc in the presence of GSH and GSSG. In vivo, MT may keep the cellular concentrations of free zinc very low and, acting as a temporary cellular reservoir, release zinc in a process that is dynamically controlled by its interactions with both GSH and GSSG. These results suggest that a change of the redox state of the cell could serve as a driving force and signal for zinc distribution from MT.The possible functional implications of the zinc cluster structure of metallothionein (MT) have been the subject of much speculation (1-3). In contrast with other zinc proteins, MT is remarkable in that it binds zinc with high thermodynamic stability [K d ϭ 1.4 ϫ 10 Ϫ13 M at pH 7.0 for human MT (4)] while exhibiting a kinetic lability that results in facile zinc exchange reactions (5). This unusual combination appears to be a characteristic property of the clusters and, likely, a critical element in their hypothetical function to ''[provide] zinc where and when needed and for whatever role'' (6). Thus, in MT the protein plays a role in the biological function of zinc, a paradigm quite different from that in most other zinc proteins where zinc plays a role in the biological function of the protein. The tight binding of zinc to MT raises questions of how it is released and whether or not the release is controlled. In this regard, we have identified glutathione disulfide (GSSG) as a cellular ligand that reacts with MT and mobilizes zinc, resulting in the suggestion that the zinc content of MT is linked to the redox state of glutathione in the cell in such a manner that zinc remains bound to MT as long as high thiol reducing power prevails and is released once the redox balance becomes more oxidizing (7). We here extend these findings by studying the role of glutathione-mediated zinc release in the presence of a zinc acceptor such as an apoenzyme. In particular, we show that only one of the seven zinc atoms i...

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“…Sorbitol dehydrogenase (SDH) has some structural properties resembling those of mammalian and yeast alcohol dehydrogenases (ADHs) (1). All these enzymes have subunits ofsimilar size range, are sensitive to the same types of inhibitor, and contain reactive cysteine residues in similar structures, including one ofthe zinc ligands at the active site ofhorse liver ADH (LADH), (2).…”

mentioning

confidence: 99%

Alcohol and polyol dehydrogenases are both divided into two protein types, and structural properties cross-relate the different enzyme activities within each type.

Jörnvall¹,

Persson²,

Jeffery³

1981

Proc. Natl. Acad. Sci. U.S.A.

220

104

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Sorbitol dehydrogenase from sheep liver shows similarities to mammalian and yeast alcohol dehydrogenases.Comparisons based on peptides from segments of sorbitol dehydrogenase reveal that homologous regions with 38% identity include two ligands to the active site zinc atom in liver alcohol dehydrogenase, as well as further important residues. Similarities in other regions are less extensive, exactly as they are between different alcohol dehydrogenases. In all aspects, sorbitol dehydrogenase appears as a typical member of the alcohol dehydrogenase family. On the other hand, alcohol dehydrogenase from Drosophila, which has a shorter subunit, is not closely related to either of these enzymes, except for a region that probably corresponds to the first part ofthe coenzyme binding domain in many dehydrogenases. Instead, Drosophila alcohol dehydrogenase in its supposed catalytic region shows similarities toward Klebsiea ribitol dehydrogenase, which also has a small subunit. It may be concluded that both alcohol and polyol dehydrogenases show two types of protein subunit, reflecting an early subdivision of polypeptide types into "long" and "short" subunits rather than into different enzymatic specificities or quaternary structures. The relationships explain Imown properties of all these enzymes and provide insight into functional mechanisms and evolutionary interpretations.Sorbitol dehydrogenase (SDH) has some structural properties resembling those of mammalian and yeast alcohol dehydrogenases (ADHs) (1). All these enzymes have subunits ofsimilar size range, are sensitive to the same types of inhibitor, and contain reactive cysteine residues in similar structures, including one ofthe zinc ligands at the active site ofhorse liver ADH (LADH), 4226The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.

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Properties of Sorbitol Dehydrogenase and Characterization of a Reactive Cysteine Residue Reveal Unexpected Similarities to Alcohol Dehydrogenases

Cited by 55 publications

References 38 publications

Extensive variations and basic features in the alcohol dehydrogenase – sorbitol dehydrogenase family

Extensive variations and basic features in the alcohol dehydrogenase – sorbitol dehydrogenase family

The glutathione redox couple modulates zinc transfer from metallothionein to zinc-depleted sorbitol dehydrogenase

Alcohol and polyol dehydrogenases are both divided into two protein types, and structural properties cross-relate the different enzyme activities within each type.

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