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The catalytic inactivation of the N-half of human hexokinase 2 and structural and biochemical characterization of its mitochondrial conformation.

Abstract：

:The high proliferation rate of tumor cells demands high energy and metabolites that are sustained by a high glycolytic flux known as the 'Warburg effect'. The activation and further metabolism of glucose is initiated by hexokinase, a focal point of metabolic regulation. The human hexokinase 2 (HK2) is overexpressed in all aggressive tumors and predominantly found on the outer mitochondrial membrane, where interactions through its N-terminus initiates and maintains tumorigenesis. Here, we report the structure of HK2 in complex with glucose and glucose-6-phosphate (G6P). Structural and biochemical characterization of the mitochondrial conformation reveals higher conformational stability and slow protein unfolding rate (ku) compared with the cytosolic conformation. Despite the active site similarity of all human hexokinases, the N-domain of HK2 is catalytically active but not in hexokinase 1 and 3. Helix-α13 that protrudes out of the N-domain to link it to the C-domain of HK2 is found to be important in maintaining the catalytic activity of the N-half. In addition, the N-domain of HK2 regulates the stability of the whole enzyme in contrast with the C-domain. Glucose binding enhanced the stability of the wild-type (WT) enzyme and the single mutant D657A of the C-domain, but it did not increase the stability of the D209A mutant of the N-domain. The interaction of HK2 with the mitochondria through its N-half is proposed to facilitate higher stability on the mitochondria. The identification of structural and biochemical differences between HK2 and other human hexokinase isozymes could potentially be used in the development of new anticancer therapies.

journal_name

Biosci Rep

journal_title

Bioscience reports

authors

Nawaz MH,Ferreira JC,Nedyalkova L,Zhu H,Carrasco-López C,Kirmizialtin S,Rabeh WM

doi

10.1042/BSR20171666

subject

Has Abstract

pub_date

2018-02-21 00:00:00

issue

1

eissn

0144-8463

issn

1573-4935

pii

BSR20171666

journal_volume

38

pub_type

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