Protein Role In Human Disease Biology Essay

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A blast (basic local alignment search tool) is capable of searching all the available sequence databases. The default database is maintained by NCBI and its lack of redundant sequences for the same species accelerates the analysis of the BLAST output file. (Westhead et al., 2002). Even though the NR database happens to be the default database for a simple blast run, the user still has the option of selecting the database of their choice. Similar sequence to a query can be established in a database by aligning it to each database sequence in turn and returning the highest scoring which involves the most similar sequence (Westhead et al.,2002). The NCBI (National Center for Biotechnology Information) is a collection of quite a lot of public domain database and search tools that is available through the internet and is compatible with most Web browsers. A suitable programmer can be selected, for instance in the case of the NCBI a program is need to conduct a simple sequence similarity search, then one of the BLAST (programs might be appropriate.

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In this study we were give a nucleotide and we had to identify the protein that the sequence codes for by using "Basic Local Alignment Search Tool" (BLAST) from the NCBI (www.ncbi.nlm.gov/blast).

Hyaluronidase is an enzyme intracellular hydrolyses hyaluronan a large non-sulfate glycosaminoglycan. It has been identified that several human genes code for hyaluronidase and its role has recently been emphasized in invasion of prostate cancer, colonic cancer and breast cancer (Wang et al.2009). Hyaluronidase (HYAL 1) codes for an mRNA that is identical to uncharacterised gene. This gene was localised in chromosome 3p21.2-3p21.3 in human plasma tissues in various organism include Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo. It has a molecular weight of 48237. Mutation occurs in link with mucopolysaccharides type IX or hyaluronidase deficiency.

PROTEIN ROLE IN HUMAN DISEASE:

Hyaluronic acid (HA) is the substrate of hyaluronidase and a ubiquitous component of the extracellular matrix. It regulates cell proliferation, migration and adhesion by interacting with cell surface hyaluronic acid receptors (CD44). When HA synthase coexpressed with hyaluronidase promote tumor growth and metastasis and hyaluronan accumulation in tissues (Vinata et al, 2005).

Recent findings suggested that HYAL1 gene can function either as a promoter or as a suppressor. The expression level is important since HYAL 1 can either promote or suppress malignant growth in a single cell type depending on the resulting enzyme activity. As a suppressor was noted where in an invasive bladder cancer cell blocked HYAL1 expression and decreased tumor growth, inhibited tumor infiltration and decreased microvessel density. Increased hyaluronidase expression in prostate, colon and breast tumor was also reported. (Vinata et al, 2005)

A strong relationship between HYAL1 and HYAL2 mRNA expression has been noticed in recent studies. These two genes are located in 3p21.3 chromosome region; it's common for imbalance allelic to occur. The status of the chromosome 3p21.3 locus determines the HYAL mRNA expression. HYAL1 and HYAL 2 are major mammalian hyaluronidase in somatic tissues; they act by degrading high molecular weight hyaluronan to the tetrasaccharides. HYAL1 is the only hyaluronidase in mammalian plasma and urine and found at high levels in organs such as liver, spleen, heart and kidney. It has an additional retained intron within exon 1 it is not present in other HYALs sequences. Hyaluronan (HA) fragments are produce at the cell surface in endocytic vesicles. Resulting from digestion by the GPI-anchored HYAL2 in acidic environment, an unknown process transported HYAL2 intracellular and then further digested by HYAL1. HYAL1 is not able to bind extracellular HA in neutral pH. However the degradation of HA happens by the action of HYAL1 and HYAL2 and 2 exoglycosaccharides (β-glucoronidase and β-N-acetylglucosaminidase) that remove sugars from the reducing termini of HA oligomers (Csoka et al, 2001).

High levels of hyaluronan (HA) occur in inflammation, stroke, and the swelling following organ transplantation and in carcinogenesis. Hyalurodinase control mechanism is critical in normal and abnormal biology, the sudden change of catabolic turnover and the modulation of hyaluronidase activities provides vast response mechanism for changing levels of HA, rather than the synthetic reactions (Csoka et al, 2001)

HYAL1 deficiency causes mucopolysaccharidosis IX. A patient was medically examined and was found that the phenotype were normal, however there were some retardation growth, bilateral-peri and intra-articular soft tissue masses, transient painful swelling of the masses with irregular effusions and widespread swelling. The ultra-structural showed histiocytes filled with various large membrane-bound vacuoles suggesting of a lysosomal storage disease. (Csoka et al, 2001).

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Accumulation of HA is caused by the loss of hyaluronidase activity and maybe this is one of the steps allowing cells in multi-step process of carcinogenesis. Hyaluronan has been raised as mechanism for tumor invasion and metastatic spread. Tumor aggression and poor outcome often linked with high levels of HA surrounding the tumor cell. Overproduction of HA increases anchorage-independent tumor cell growth. Hyalurominidase would qualify as tumor suppressor gene products (Csoka et al, 2001). HYAL1 gene is located within tumor suppressor gene locus, defined by homozygous deletions and by functional tumor suppressor activity. Only two missense mutations in HYAL1 have been reported in carcinoma, usually in neck, head and oral carcinomas. Mutation occurs when one of the 2 alleles is lost and the remaining allele homozygous loss would be necessary. PCR found a large 5'UTR as a lesion that produce functional silencing of the HYAL1 gene product in some oral cancer. Neither hyaluronidase enzyme activity nor HYAL1 protein could be detected through mRNA for HYAL1 in a few of cancer cells (Csoka et al, 2001). This indicated a presence of a retained intron; it prevented translation due to the large number of start codon and stop codon present. The mode of gene silencing in carcinoma is not unknown. Metabisulfite sequencing that correlates with loss of gene expression, identified hypermethylated CpG nucleotides in the 5' HYAL1 promoter region. Depression of gene to normal level in cells requires a treatment such as demethylating agents and histone deacetylase inhibitors (Csoka et al.2001). These findings have shown the importance of the loss hyaluronidase in the process of cancer development and multiple pathways of gene silencing. Cancer cells have broad ways of mechanisms for silencing unwanted gene products. Silencing tumor suppressor can occur in both levels of DNA and mRNA (Csoka et al, 2001).

In contrast Vinata et al, study showed that blocking HYAL1 expression reduces tumor growth and invasion. HYAL1 levels in different cancers are linked with high-grade invasive tumors. However, chromosome region 3p21.3 that contains HYAL1, HYAL2 and HYAL3 genes is deleted in some cancer lines. While the tumor suppressor gene in 3p21.3 is not HYAL1, HYAL2 or HYAL3, it initially rise the idea that hyalurodinase is a tumor suppressor. Jacobson et al, found in rat colon carcinoma line that the over expression of HYAL1 by cDNA transfection decreases tumor growth, although tumors are angiogenic (Vinata et al, 2005). In a study of Shuster et al, injected high dose of bovine testicular hyalurodinase in MDA435 of breast cancer xenografts and observed a decrease in tumor growth for a period of 4 days, the effect of HYAL1 on tumor growth and invasion is concentration dependent. HYAL1 expression decrease tumor growth and invasion and moderate HYAL1 express in tumor cell increases their proliferation and invasive potential, by degrading the hyaluronic acid matrix (Vinata et al, 2005). Hyaluronic acid synthase 2 and 3 are involved in tumor growth and metastasis and so is hyaluronic acid receptor RHAMM. Blocking hyaluronic acid synthase 3 expression in prostate cancer cells decrease cell growth in vitro and tumor growth in vivo. Whereas hyaluronic acid synthase 2 in the absence of hyaluronidase decrease tumor growth in glioma cells. The interaction between RHAMM and hyaluronic acid fragments make the mitogen-activated protein kinase pathway and over expression of RHAMM are a useful prognostic indicator in breast cancer (Vinata et al, 2005). Vinata et al, concluded that the hyaluronic acid- hyaluronidase system involved in the regulation of tumor growth and invasion.

OVERVIEW OF THE DATABASE:

Overall this tool is very helpful, in that it's easy to use and it's less time consuming in producing reliable results. A drawback associated with this tool is when dealing with large quantities of data and it creates difficulties in managing and interpreting the data obtained. Furthermore there is one potential problem usually associated with iterative databases searches. This is the contamination with unrelated sequences. If the hits from any one iterations of BLAST contain a false positive then the given sequence will affect all further iterations with its own relative that are not relatives of the original query (Westhead et al., 2002).The NCBI major role is to create automated machines that can analyse and store data pertaining to genetics, biochemistry and molecular biology, analyse genes or products of interest and predict the structure of the molecules analysed (enzymes). It made easy to obtain database and analytic software to the scientific community such as medical staff and researchers, and students.

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