Gleis Week 11

GO Terms

Metacyclic: produced in an intermediate host, and infective for the definitive host; said of the infective stages of trypanosomes. http://medical-dictionary.thefreedictionary.com/metacyclic

Promastigote:The flagellate stage of a trypanosomatid protozoan, as that of any of the Leishmania parasites http://medical-dictionary.thefreedictionary.com/promastigote

Phagolysosome:a cytoplasmic body formed by the fusion of a phagosome, or ingested particle, with a lysosome containing hydrolytic enzymes. The enzymes digest most of the material within the phagosome http://medical-dictionary.thefreedictionary.com/phagolysosome

Tripartite:having three corresponding parts or copies http://www.merriam-webster.com/dictionary/tripartite

"Repeated-repeat": repeated tandem repeats, Copies of DNA sequences which lie adjacent to each other in the same orientation (direct tandem repeats) or in the opposite direction to each other http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Tandem+Repeat

bacterial clade:Related organisms descended from a common ancestor. For example, isolate M of HIV-1 (the human immunodeficiency virus) consists of at least ten clades. Imported from the Greek, klados, branch in 1911 in reference to the Tree of Life. http://www.medterms.com/script/main/art.asp?articlekey=22233

filarial:related to or infested with or transmitting parasitic worms especially filaria http://wordnetweb.princeton.edu/perl/webwn?s=filarial

trypanosomatid:common name for a member of the family Trypanosomatidae http://medical-dictionary.thefreedictionary.com/trypanosomatid

chromodomain:Chromodomains are highly conserved sequence motifs that have been identified in a variety of animal and plant species. A chromodomain harbours a methylated lysine residue. http://www.springerreference.com/docs/html/chapterdbid/34668.html

bromodomain:Protein containing at least one bromodomain. The bromodomain is a conserved region, approximately 70 amino acids, characteristic for a class of regulatory proteins. It mediates interactions with proteins that are necessary for transcriptional activation. http://www.uniprot.org/keywords/KW-0103

Reference Article Outline

I. Abstract

• Leishmania major causes leishmaniasis, a dreadful human disease found throughout the world.
• Many genes currently studied involved the pathogenic nature of Leishmania major
• The lack of certain genes in the genome of Leishmania suggest novel expression and regulation systems

II. Introduction

• Leishmania parasites are transmitted by sand flies
• Once Leishmania have infected the host, the parasite subsequently proliferates and spreads throughout the host.
• Different Leishmania species exhibit differences in genome composition and structure
• This article presents the structure and content of the Leishmania major genome
• Special emphasis is given to fundamental molecular processes and pathogen-speicific functions

III. Genome structure and content

• Shotgun sequencing was used to sequence the genome chromosome by chromosome
• Table 1 is a summary of genome information for Leishmania. It includes size and gene information
• Table 2 includes information regarding families of genes in the Leishmania genome
• Several algorithms were used to predict the number of genes of each type in the genome
• Many genes in Leishmania major resemble genes other Leishmania species
• Some genes appear to be Leishmania major specific
• The Leishmania genome contains genes for MIFs which are likely responsible for the promotion of parasite survival in the host.

IV. RNA genes

• RNA participate in many important cellular processes
• RNA genes are similar between Leishmania species but their organization in the genome varies
• The genomes of Leishmania species demonstrate similarity in RNA composition and function

V. Chromatin remodeling

• Chromatin remodeling genes are distributed throughout the genome in L. major as opposed to clustering in other species
• The L. major genome contains several genes responsible for various histone modifications as well as chromatin modifications
• The modifications include acetylation and methylation

VI. Transcription

• The Leishmania major genome demonstrates unique gene clustering
• Transcription initiation in L. major is not fully understood but transcription appears to begin bidirectionally in strand-switch regions
• The genomes of Leishmania species lack components of genes encoding for RNA polymerase
• The genes for RNA polymerase vary greatly from other species
• Few homologs were found for RNA polymerase transcription factors
• Figure 1 provides a graphical image of Leishmania RNA polymerase subunits and transcription factors
• The genes located in the genome suggest post transcriptional control mechanisms as the primary determinants of gene expression
• Figure 2 provides information on the association of protein domains and gene expression regulation
• The bar graph demonstrates individual genome sequence similarity for protein domains

VII. RNA Processing

• mRNA processing is unique trypanasomatids
• However, many spliceosome proteins were identified in the genome
• Advanced splicing regulatory protein networks were identified suggesting early evolutionary development
• Two distinct, dissimilar poly(A) polymerases were identified
• The absence of certain polymerase domains reflects the polycistronic transcription of the organism
• Genes playing a role in mRNA degradation have been identified and appear similar to mammalian genes
• Leishmania lacks regulation and specificity of these mRNA degrading proteins
• A high number of RNA recognition motifs furthers suggest polycistronic transcription
• A novel domain was identified in these RNA binding proteins

VIII. Translation and post translational modification

• Genes encoding translation machinery are similar to that of other lower Eukaryotes
• Relatively high number of translation factors suggests high degree of specialization
• The genome encodes for typical protein modification processes
• A particularly high number of genes encode for enzymes that produce certain protein modifications
• These enzymes could be potential drug targets

IX. Surface Molecules

• Surface molecules are particularly important for Leishmania due to infectious processes requiring these molecules
• Many genes encoding for these surface molecules appear to be novel and have not been completely identified
• Some of these molecules are assembled in the lumen of the golgi due to a need for sugar assembly
• L. major specific genes have been identified for these processes
• Some of these genes are clustered together on the genome
• The primary sphingolipid in Leishmania is IPC
• This is not produced in mammals and is therefore and excellent drug target
• The major insect stage surface protein of Leishmania is GP63 which is a zinc metallopeptidase
• Surface proteins appear to be expressed variably with development
• L. major shares surface molecule similarity to other related species

X. Proteolysis

• Peptidases are very diverse and are characterized by evolutionary similarity
• L. major lacks certain peptidases common to other parasites but share similarities to other Leishmania species
• Exhibit nonlysosomal protein degradation through ubiquitin
• Cell death through caspase independent mechanism
• No trypsin/chymotripsin
• Other serene peptidases present as well as other metallopeptidases other than GP63
• Lack certain peptidase inhibitors but exhibit inhibitors not present in mammals
• Produce inhibitors of peptidases to aid in infection of host

XI. Conclusion

• Leishmania genomes share many similarities but genomic differences express important factors that enable specific functioning of the organism
• Genomic data provides important insight to drug targets for Leishmanaiasis