Sandbox GGC2

1QHA HUMAN HEXOKINASE TYPE I

spinqualitylabelsall models HUMAN HEXOKINASE TYPE I COMPLEXED WITH ATP ANALOGUE AMP-PNP Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Function Human Hexokinase 1 '1QHA' falls under the protein category of a kinase and is located within the cytosol and along the mitochondrial outer membrane . A kinase is a protein that is responsible for the modification of a molecule through the covalent addition of the phosphate group. The source of the phosphate group is Adenosine Triphosphate (ATP). Human Hexokinase 1 catalyzes the phosphorylation of hexose sugars, primarily Glucose to form Glucose-6-Phosphate. This is typically observed during the initial step of glycolysis and is performed in order to attach a charge to the glucose, preventing it from diffusing out of the cell through the cell membrane. Typically, a Magnesium cofactor also participates in a chelation complex with ATP . Human Hexokinase 1 is seen to have a function in both innate immunity and inflammation in which the protein acts as a pattern recognition receptor for N-acetyl-D-glucosamine, a hexose present in the peptidoglycan layer of bacterial cell walls. Upon binding to N-acetyl-D-glucosamine, Human Hexokinase 1 dissociates from the mitochondria, which results in the activation of NLRP3 inflammasome . Human Hexokinase 1 is also seen to play a role in tumor suppression. It does so by form a complex with voltage-dependent anion channel-1 (VDAC1) when acted phosphorylated by activating transcription factor 2 (ATF2). The HK1-VDAC1 complex functions to increase the permeability of the mitochondria outer membrane. This causes a release of mitochondrial enzymes which trigger apoptosis . Disease There are multiple diseases associated with Human Hexokinase 1. It is possible for illness to arise from a deficiency in the protein. A deficiency is a rare autosomal recessive disease in which the Leucine and Threonine residues in the 529 and the 680 positions are mutated and translated as a Serine. This disease results in nonspherocytic hemolytic anemia . Also, diseases of Human Hexokinase can also result in diseases that affect the nervous system. A nervous system disease associated with the protein is neuropathy, hereditary motor and sensory, Russe type (HMSNR), also known as Charcot-Marie-Tooth disease. Laboratory studies suggest that this disease is caused by a mutation in a 26 kb range in upstream exons in the Human Hexokinase 1 gene. HMSNR is also autosomal recessive and is usually apparent in the first 10 years of life, characterized by muscular atrophy and impairment in the distal lower limbs. This weakness and atrophy results in those affected by the disease experiencing difficulty walking. HMSNR can later develop into weakness in the distal upper limbs and the proximal lower limbs. It is suspected that this disease is a result of demyelination of the neuronal axon which in turn has negative effects on neuron action potential velocity . Another nervous system disease is a neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA). This disease is found to primarily impact the brain, eyes, and heart. NEDVIBA is characterized by speech delay, intellectual disability, structural brain abnormalities, and visual impairments. The disease is caused by mutations in the 414 position (G → E), the 418 position (K → E), the 445 position (S → L), and in the 457 position (T → M) . Retinitis pigmentosa is also a disease caused by mutation of the Glutamate residue in the 847 positions to a Lysine in Human Hexokinase 1. This disease is an autosomal dominant disease. Retinitis pigmentosa is a form of retinal dystrophy and is characterized by retinal pigment deposits. There is also a loss of both the rod and cone photoreceptors in the eye. Patients typically experience visual difficulty in poorly lit environments and loss of the mid-peripheral visual field. As the condition progresses, patients continue to experience deterioration of the visual field . Structural highlights The Human Hexokinase 1 protein is a homodimer formed from an "A" chain and "B" chain. There are only a few post-translational modifications that the Human Hexokinase 1 protein undergoes, those being acetylation at the Methionine residue in the 1 position and phosphorylation of the Serine residue in the 337 position, a modification that is also seen in the Rattus norvegicus (Rat) variation of the gene . This serine phosphorylation results in the presence of a phosphoserine. There are several relevant regions of importance in the Human Hexokinase 1 protein. The N-terminal spanning from residue 1-10, are responsible for the binding interaction between the Human Hexokinase 1 protein and the mitochondria. Further, there are multiple Glucose-6-Phosphate binding domains. These binding domains are seen at residues 84-91, 413-415, 532-536, and 861-863. There are also multiple glucose binding sites present at residues 172-173, 208-209, and 291-294 .