Histidine Synthesis: An Overview of Research

Histidine Synthesis: An Overview of Research Histidine Synthesis Kathryn McCallister The study of the biosynthetic pathway leading to synthesis of the amino acid histidine in prokaryotes and lower eukaryotes was begun more than 40 years ago and has resulted in the unraveling of many fundamental mechanisms of biology (1). With this it can be assumed that much of the pathway is known or is in the process of becoming known. What is to be discussed is the pathway itself, which has been studied extensively in E. coli and S. typhimurium. While many may not understand why this pathway is important in the body it should not be understated that this is a very important pathway. Histidine is an essential amino acid. Histidine metabolism has been extensively researched and many articles have been published about the numerous effects of having deficient or excessive histidine in the blood. This paper will go over the flow of the pathway in detail from the beginning to the end result, Histidine. Histidine is something that is very important in the human body and this will be rev ealed later in the paper. Now the portion of the pathway to be discussed is the portion in which Histidine is made into Carnosine. Now in order to discuss this portion of the pathway we must first find out how we make Histidine in the first place. This pathway also occurs in prokaryotes which are the main organism in which this pathway has been studied. The disease that we will be focusing on is Carnosinemia. This disease is caused by a deficient amount of histidine in the body. Lastly we will discuss the prevalence of this disease in society and how this could potentially affect the population in the future. The histidine system is an important system in the body. It has also helped with other theories. The histidine system was of the utmost importance in the definition and refinement of the operon theory (1). In order to understand this theory you first must understand what an operon is. An operon contains a group of genes that code for enzymes involved in a metabolic pathway (2). This is very important in the processes of the organism. The operon helps the cell conserve energy. The operon theory was first proposed by the French microbiologist Franà §ois Jacob and Jacques Monod in the early 1960s (2). While this seems irrelevant in fact, it has been calculated that 41 ATP molecules are sacrificed for each histidine molecule made (1). With that kind of energy needed it’s no wonder that the majority of Histidine comes from diet. Histidine is a costly amino acid to produce, so in order for the body to maintain itself it has to be able to take Histidine from the food in which we eat . If enough of this amino acid is not taken in then it could potentially cause problems. Histidine is one of the most important substances in the body only because it can be converted into other things one of which is really important in the body, haemoglobin. Furthermore, it is involved in various metabolic reactions and hence ensures indirectly the oxygen supply to all the organs and tissues (3). Without oxygen the body would eventually begin to shut down. In particular, in the well-known yeast S. cerevisiae, the seven genes responsible for the biosynthesis of histidine are located on six different chromosomes (1). Now this is very different than in Archaebacteria. The his genes in archaebacterial are less well known than in eubacteria; only three his genes have been recognized in just four species, three of them belonging to the genus Methanococcus and one to Halobacterium (1). This is interesting since there are seven genes. The demonstration that hisI and hisE is, in fact, a single gene (now hisI) brought the genes to eight and the steps to 10 (1). Quickly covering these steps is no easy task, but below is an attempt to do so. The first reaction in histidine biosynthesis is the condensation of ATP and 5-phophoribosyl 1-pyrophosphate (PRPP) to form N’-5’-phosphoribosyl-ATP (PRATP) (1). This key reaction is involved in feedback inhibition. The second step in histidine biosynthesis is the condensation of PRATP into PRAMP. From PRAMP the synthesis produces BBMII. The fourth step of the pathway is an internal redox reaction, also known as Amadori rearrangement, involving the isomerization of the aminoaldose 5’-ProFAR to the aminoketose N’-[(5’-phosphoribulosyl)-formimino]-5-aminoimidazole-4-carboxamide-ribonucleotide (5’-PRFAR or BBMIII) (1). This is then synthesized into imidazole-glycerol-phosphate, also known as IGP. AICAR, which is produced in the reaction catalyzed by the IGP synthase, is recycled into the de novo purine biosynthetic pathway (1). From there it is dehydrated and the resulting enol is ketonized nonenzymatically to imidazole-acetol-phosphate (IAP) (1). The seventh step of this pathway is a reversible one in which IAP is involved. The reaction leads to the production of ÃŽ ±-ketoglutarate and L-histidinol-phosphate (HOL-P) (1). From there it loses the phosphate and becomes L-histidinol (HOL). HOL is oxidized and becomes L-histidinal, which is an unstable portion of the pathway. From there it proceeds to histidine by way of a transferase, or in other words it moves the intermediate to another site on the chain. Nevertheless, the two initial substrates of histidine biosynthesis, PRPP and ATP, play a key role in intermediate and energetic metabolism and link this pathway to the biosynthesis of purines, pyrimidines, pyridine nucleotide, folates, and tryptophan (1). Klem and Davisson found that the protein encoded by the hisF gene has an ammoni-dependent activity that is responsible for the conversion of PRFAR to AICAR and IFP, while the product of the hisH gene had no detectable catalytic properties. However, in combination, the two proteins were able to carry out the reaction in the presence of glutamine as a nitrogen donor without releasing any free metabolic intermediate (1). Final identification was generally achieved from DNA and protein sequence comparison with the E. coli counterparts, assuming, as it is widely accepted, the the biosynthetic pathway is fundamentally the same in all organisms (1). This later may be associated with dietary factors, since it is known that histidinuria may be present after a heavy protein meal especially in children; it is also increased during pregnancy and at the beginning of the luteal phase of the menstrual cycle (9). This is interesting to note because this study was done in 1962 ns was based on a urine analysis of the mentally defective population of Northern Ireland. This study proposed that there were approximately 4,000 people under the care of the Northern Ireland Hospitals Authority during this study. In the 2,081 urines examined there were two cases of very severe generalized aminoaciduria and 36 cases of moderate severity; these latter are of ‘central cluster’ pattern involving glycine, serine, alanine, glutamine and/or glutamic acid, histidine, threonine and sometimes taurine (9). While these numbers may seem insignificant when you take that throughout the whole population who may not know that they have a deficiency, t he numbers translate to 1.8% of the population. It is appreciated that many of the above amino-acidurias may have a metabolic basis quite unrelated to mental retardation, and it is hoped to study these cases in detail (9). This is later confirmed by further testing. The portion of the pathway that will be discussed is from Histidine to Carnosine. This may seem unrelated but Carnosinemia is caused by a lack of Histidine because it is partially made up of Histidine. Without Histidine there can be no Carnosine made. One of the genes that have recently been linked to diabetic nephropathy is Carnosine dipeptidase-1 (6). This is just one of the problems that carnosinemia could potentially cause in the human body. In humans, circulating Carnosine is readily degraded by the highly active serum carnosinase enzyme, which is secreted from the liver into the plasma (6). Without Carnosine this enzyme isn’t able to function properly. Carnosinase is a true dipeptidase and this was discovered in an experiment that was published in 1985. Human tissue carnosinase (EC 3.4.13.3) had optimum activity at pH 9.5 and was a cysteine peptidase, being activated by dithiothreitol and inhibited by p-hydroxymercuribenzoate (7). While pH may be manipulated in a lab, ou r body adjusts our pH everyday on a cellular level in order to work at maximum capacity at all times. Carnosine could hold the potential to protect type 2 diabetics from some of the complications associated with nerve damage. From these genetic data in human patients, it was hypothesized that L-Carnosine serum levels are associated with the risk for late complications of diabetic disease and that L-Carnosine acts as a protective factor (6). This is interesting to note since most symptoms associated with low amino acid levels involve some sort of nerve problem. The researchers hypothesized that L-Carnosine may be a protective factor when it comes to diabetic patients and their potential nerve problems associated with type 2 diabetes. In the results they found that mice that were supplemented with L-Carnosine had later onset diabetes and was much milder than anticipated. Their conclusion was that hCN1-dependent susceptibility to diabetic nephropathy may at least in part be mediated by altered glucose metabolism in type 2 diabetic patients (6). It has been found that Carnosine not only protects against type 2 diabetes but also with LDL and high cholesterol. In an experiment published in 2007 it was found that Carnosine was able to lower LDL without the dangerous accumulation of cholesterol that many drugs on the market cause. The key finding of the current study is that Carnosine and its constituents are effective at equimolar concentrations to the modifying agent, out data suggests that Carnosine and its constituents may serve as effective scavengers of carbonyl compounds and inhibitors of protein glycation in vivo, and as potential therapeutic agents to inhibit diabetes-induced atherosclerosis. (5). That is why Carnosine is so important in the human body. Now managing this disease isn’t as simple as just ingesting more histidine or Carnosine. There is no known cure for carnosinemia. They are still trying to figure out what causes carnosinemia. The signs and symptoms of carnosinemia are: aminoaciduria, cognitive impairment, developmental regress, EEG abnormality, seizures, autosomal recessive inheritance, carnosinuria, generalized myoclonic seizures, and intellectual disability (12). Most of the symptoms as stated have to do with the brain and its functions, and this is very similar to a number of other diseases that have to do with amino acid deficiency. Unfortunately as stated there is no known cure or management for this disease. Unfortunately only about 30 cases have been reported to date so not a lot of people even know that this disease exists. So far, all genetically determined diseases due to primarily to an enzyme deficiency are inherited by recessive or sex-linked mechanisms and this rule is holding so well that there is little reason to search for such a cause in conditions showing dominant inheritance (4). Carnosinemia is an autosomal recessive disorder, meaning that both parents have to be carriers in order for the child to be effected. The commonest approach has been to provide a diet deprived of an offending constituent, the greatest experience having been obtained with the treatment by this means of phenylketonuria and galactosaemia (4). When researched no known treatment could be neither found, nor any experimental treatments for this disease. Not enough people suffer from this disease to make experimentation worthwhile for scientists. Dietary restriction is by no means the only approach to therapy and in disorders of many essential amino-acids may not even be feasible (4). Such is the case for carnosinemia and h istidine deficiency. In conclusion, the study of histidine has spanned more than 40 years and is still very much ongoing. The two main study specimens that have been used to study the Histidine pathway are E. coli and S. typhimurium. The pathway is comprised of 10 steps in which it starts at ATP and ends with Histidine. From there is can be transformed into a number of different compounds including Histamine and Haemoglobin. There are seven genes that make up the Histidine pathway and they are located on six different chromosomes in eukaryotes. Histidine intake is mostly dietary because it is so costly for the body to make it. Which is why Histidinuria is found especially in children and pregnant women. They also found the Histidine deficiency can cause many developmental delays, and was found in a some of the mentally challenged people tested in Northern Ireland. Histidine makes up Carnosine in the human body which is very important for those with diabetes. It has been found that Carnosine may have a pr otective factor for those with type 2 diabetes. It may prevent those with type 2 diabetes from developing a severe case of nephropathy. It was also found to help lower LDL without causing cholesterol buildup like some of the drugs on the market today. This is why Carnosine is so important in the human body. Carnosinemia is a very serious disease and there is no known cure or treatment for it. The symptoms of Carnosinemia range from cognitive impairment to seizures. Unfortunately this disease can’t be fixed with diet, and there are no known medications or treatments for this disease. Carnosinemia is a very serious disease caused by a deficiency of Histidine. References Alifano, P.; Fani, R; Lià ², P.; Lazcano, A.; Bazzicalupo, M.; Carlomagno, M. S.; Bruni, C.B. Histidine Biosynthetic Pathway and Genes: Structure, Regulation, and Evolution. Am. Soc. For Microbiology. 1996, Vol. 60, 44-69. Encyclopedia Britannica. Operon. http://www.britannica.com/EBchecked/topic/429974/operon (accessed Nov 25, 2014). Amino Acid Studies. L-histidine. http://aminoacidstudies.org/l-histidine/ (accessed Nov 25, 2014). Raine, D. N. Management of Inherited Metabolic Disease. British Medical Journal. 1972, Vol.2, 329-336. Rashid, I.; van Reyk, D. M.; Davies, M. J. Carnosine and its constituents inhibit gylcation of low-density lipoproteins that promotes foam cell formation in vitro. Federation of European Biochemical Societies. 2007, 1067-1070. Sauerhofer, S.; Yuan, G.; Braun, G. S.; Deinzer, M.; Neumaier, M.; Gretz, N.; Floege, J.; Kriz, W.; van der Woude, F.; Moeller, M. J. L-Carnosine, a Substrate of Carnosinase-1, Influences Glucose Metabolism. Diabetes. 2007, Vol. 56, 2425-2432 Lenner, J. F.; Pepper, S. C.; Kucera-Orallo, C. M.; George, R. P. Characterization of human tissue carnosinase. Biochem. J. 1985, 653-660. Everaert, I.; Taes, Y.; De Heer, E.; Baelde, H.; Zutinic, A.; Yard, B.; Sauerhofer, S.; Vanhee, L.; Delanghe, J.; Aldini, G.; Derave, W. Low plasma carnosinase activity promotes carnosinemia after Carnosine ingestion in humans. American Physiological Society. 2012, F1537-F1544. Carson, N. A. J.; Neill, D. W. Metabolic Abnormalities Detected in a Survey of Mentally Backward Individuals in Northern Ireland. Archives of Disease in Childhood. 1962, 505-513. Kanehisa Laboratories. Histidine metabolism-Reference pathway. http://www.genome.jp/kegg-bin/show_pathway?org_name=mapmapno=00340mapscale=show_description=hide (accessed Nov 25, 2014). University of Bristol. Histamine in the body. http://www.chm.bris.ac.uk/motm/histamine/jm/body.htm (accessed Nov 25, 2014). National Center for Advancing Translational Sciences. Carnosinemia. http://rarediseases.info.nih.gov/gard/6001/carnosinemia/resources/9 (accessed Nov 30, 2014). Orpha. Prevalence of rare disease: Bibliographic data. Orphanet Series [online] 2014, 8 http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf

High School and Exemption Forms

I am in the process of distributing Exemption Forms to students today. I wanted to go over a few things with you so that we are all on the same page. Exemptions were put into place to encourage and reward good attendance and behavior. This is not a privilege entitled to every student simply because they are enrolled in our school†¦ It is a REWARD. Please pass this on to your students. The rules are very simple†¦. If you have been in SIS, DEEP or if you have been suspended this semester, then you can't be exempt. The average that a student must have in your class in order to be exempt is based on he number of absences that he or she has in your class. A. If a student has 0-1 excused absence in your class, their semester average must be an 80 or above B. If a student has 2 excused absences in your class, their semester average must be an 85 or above C.If a student has 3 excused absences in your class, their semester average ,must be a 90 or above If a student has an unexcused absence in your class, they may not be exempt from your test. Notes for unexcused absences will not be accepted at this point. It is the students' responsibility to turn in notes within 5 days of returning to school after they eave been absent. Please do not give the student the attendance information that you see in your grade book as this includes extracurricular absences in the total number and those do not count.

Free Printable Science Worksheets and Coloring Pages

Science is usually a high-interest topic for kids. Children love to know how and why things work, and science is part of everything, from animals and earthquakes to the human body. Take advantage of your students fascination with science-themed topics by incorporating fun printables and hands-on learning activities into your science studies.   General Science Its never too early to begin teaching children to document their scientific lab findings. Teach them to make a hypothesis (an educated guess) about what they think the result of the experiment will be and why. Then, show them how to document the results with science report forms.   Learn about the men and women behind todays science by using free worksheets, such as  Albert Einstein printables,  where students can learn about one of the most famous scientists of all time. Spend some time exploring the tools of a scientists trade, such as the  parts of a microscope. Study general science principles—that people use every day, often without even realizing it—such as how  magnets  work,  the basics of Newtons laws of motion, and the workings of  simple machines. Earth and Space Science Earth, space, planets, and the stars are fascinating to students of all ages. The study of life on this planet—and in the universe—is a topic worth delving into with your students. Students can soar into the heavens with astronomy and space exploration printables. Study the  weather  and natural disasters such as  earthquakes  or  volcanoes. Discuss the types of scientists who study those fields such as meteorologists, seismologists, volcanologists, and geologists. Spend time outdoors creating your own rock collection and indoors learning about them with  rocks printables. Animal and Insects Kids love learning about the creatures they can find in their own backyard. Spring is a great time to study the birds  and  the bees.  Learn about the  lepidopterists—scientists who study moths and butterflies—and entomologists, who study insects. Schedule a field trip to a beekeeper or visit a butterfly garden.  Visit a zoo and learn about mammals, such as  elephants  (pachyderms), and  reptiles,  such as alligators and crocodiles. If your young students are fascinated by reptiles, print a reptiles coloring book for them You may have a future paleontologist in your class or homeschool. If so, visit a museum of natural history so that she can learn about dinosaurs. Then, capitalize on that interest with a set of free  dinosaur printables. While youre studying animals and insects, discuss how the seasons—spring,  summer,  fall, and winter—affect them and their habitats. Oceanography Oceanography is the study of the oceans and the creatures that live there. Many  of the animals who call the ocean home are very unusual looking. Help students learn about the mammals and fish that inhabit the oceans, including dolphins, whales, sharks, and seahorses, as well as: CrabsJellyfishManateesOctopusesSea TurtlesStarfish Then, dig deeper by exploring more facts about dolphins, seahorses, and even lobsters. Updated by Kris Bales

The Language And Literacy Development Of The Children...

usage, family involvement and follow-up visits to schools. Qualitative and quantitative measures were used for the purpose of charting a holistic and detailed picture of the language and literacy development of the children using AAC. The goal of the study is to explore effective approaches for supporting communication (including oral language, literacy, and technology skills) among those who require AAC devices. They took part in an intensive, 4-week summer intervention program. The program was designed to explore effective approaches, content and contexts for supporting communication, including oral language, literacy, and technology skills for those who require AAC. Results indicated students using AAC benefit from the integration of†¦show more content†¦The results were found to be that the reality of inclusion was based on the lives and experiences of the people practicing it daily. Their conclusion was that while governmental policy mandates schools implement programs a specific way, when there is ambiguities regarding practice and performance (Meyers, 2007). The next study was a quantitative longitudinal study lasting 8 weeks was created to determine if the attitudes of student teachers who were taught without inclusion as a primary focus could be affected in a positive way when placed in a classroom where inclusion was the focus. The purpose of this study is twofold: first to determine if students’ attitude towards inclusion in their classroom is best gained during the educational part of the course study or in the experience portion of the credential process (Lambe Bones, 2007). It also looked to determine the key factors that can influence attitude change during the credential process, before candidates advance to student teaching. The findings of this study were that surveys given at the end of the student teaching experience showed a significant change in personal attitudes and beliefs from the first administration of the surveys. The authors conclude that students in the end stages of their credential program already had a positive attitude towards