The Creatine Kinase Enzyme Biology Essay

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Creatine kinase (CK) is an enzyme involved in the muscle contraction, which requires energy that is derived from the hydrolysis of ATP, and the levels of ATP ought to be maintained. Since ATP can be hydrolysed in few seconds, another reaction to produce more ATP is required. This is met by metabolic breakdown of creatine phosphate into creatine and ATP.

This reaction involves the action of enzyme CK:

Creatine phosphate + ADP + H+ ï‚® creatine + ATP

CK generates the amount of ATP needed for muscle contraction, by breaking down creatine phosphate into ATP and creatine. (Pocock and Richards 2006)

b. CK serum is used as indicator for muscle damages and in few case studies it was found that CK level is raised in conditions such as muscular dystrophy and malignant hyperthermia. (Nordmann et. al 2009). Ruth suffered muscle damage and this condition will cause the CK serum to flow into the bloodstream hence resulting in the increase of CK level post operatively.

(Nordmann et. Al 2009)

Problem 2

Blood pH

Rephosphorylation of ATP is catalyzed by the CK serum. The end products of this reaction are ATP and creatine. (Pocock and Richards 2006)

Creatine is made up of three amino acids; Arginine, Glycine and Methionine. (Da Silva et al. 2009). The increase of CK level will lower the blood pH due to the release of acidic creatine into the bloodstream.

Serum potassium concentration

The concentration of this serum will increase as the muscle is ruptured, hence allowing the diffusion of potassium out of the sarcoplasmic reticulum into the blood stream. (Rhoades and Bell 2009)

Serum phosphate concentration

The concentration of this serum will fall because more CK is being used to catalyse the rephoporylation of ATP reaction, hence more phosphate is being used to phoporylate the ADP molecule to ATP. This phosphate comes from the creatine phosphate molecule. (Rhoades and Bell 2009)

Serum calcium concentration

The concentration of serum calcium would increase as CK level increases. Calcium is crucial for the sliding-filament of muscle contraction. (Pocock and Richard 2006). The puncture of the muscle, would release more serum calcium from the sarcoplasmic reticulum into the myofilament space.

Problem 3

Ruth would most unlikely to experience tachycardic and cardiac arrhythmias. (Katz et al. 1993) The effect of ketamine is that it increases sympathetic nervous system activity, which is very crucial for patients who are in high need to maintain their cardiovascular function. (Grahame-Smith and Aronson 2002)

Problem 4

Caffeine and Halothane. (Malignant Hyperthermia Association United States online 2010)

Equivocal result is obtained when the test is positive for the contracture of muscle in either caffeine or halothane test. (M Vukcevic 2010).

Problem 5

Diagram of transverse tubule in skeletal muscle

Problem 6

Mutation in the RYR1 gene might not result in malignant hyperthermia unless it is triggered by administration of certain anesthetic agents like halothane and enflurane which are usually used for surgery. (Ta and Pessah 2006). There are few types of Ca2+ binding sites at the RYR1 channels; A-site and L-site. When a susceptible MH patient is exposed to certain anesthesia, the affinity of A-site towards Ca2T increases and this reaction would generate excessive heat energy and lactic acid, eventually lead to hyperthermia and lactic acidosis. (Ta and Pessah 2006)

Problem 7

Duchenne Muscular Dystrophy

King-Denborough Syndrome

Mitochondrial Myopathies

Glycogen Storage Disease

(Brownell 1988)

Problem 8

a.

5ï‚¢ - UCCGGGACGCCGAGCCGCACGAGUUCUUCU - 3

b. There are few possible polypeptide sequences that can be derived

1. 5'- CCUGUAGGAGAAGCUGGAUGUGGCCCCCAAGCGGGAUGUGGAGGGCAUGGGCCCCCCUGAGAUCAAGUACAGGGAGUCACUGUGCUUCGUGCAGCAUGUGGCCUCAGGACUGUGGCUCACCUAUGCAGCACCAGACCCCAAGGCCCAGCGGCACGGCGAGCACAAGAA-3'

Single letter protein sequence:

PVGEAGCGPQAGCGGHGPP-STOP-DQVQGVTVLVLRAACGLRTVAHLCCSRPQGPAARRAQE

(Strachan and Read 2004)

2. 5'- CUGUAGGAGAAGCUGGAUGUGGCCCCCAAGCGGGAUGUGGAGGGCAUGGGCCCCCCUGAGAUCAAGUACAGGGAGUCACUGUGCUUCGUGCAGCAUGUGGCCUCAGGACUGUGGCUCACCUAUGCAGCACCAGACCCCAAGGCCCAGCGGCACGGCGAGCACAAGAAG-3'

Single letter protein sequence:

L-STOP-EKLDVAPKRDVEGMGPPEIKYRESLCFVQHVASGLWLTYAAPDPKALRLGVLKK*

(Strachan and Read 2004)

3. 5'- UGUAGGAGAAGCUGGAUGUGGCCCCCAAGCGGGAUGUGGAGGGCAUGGGCCCCCCUGAGAUCAAGUACAGGGAGUCACUGUGCUUCGUGCAGCAUGUGGCCUCAGGACUGUGGCUCACCUAUGCAGCACCAGACCCCAAGGCCCAGCGGCACGGCGAGCACAAGAAGA-3'

Single letter protein sequence:

CRRSWMWPPSGMWRAWAPLRSSTGSHCASCSMWPQDCGSPMLLQTPRPCGSACSRR (Strachan and Read 2004)

Based on the second(2) protein derived, it can be deduced that the type of mutation is single base substitution. The 22th amino acid base is R(arginine) instead of G(glycine).

(Strachan and Read 2004)

The mutation results in different polypeptide chain formed. This would most likely affect the function of the gene produced.

(Strachan and Read 2004)

Problem 9 (Strachan and Read 2004)

Grandfather Grandmother Grandfather Grandmother

Genotype: RR Genotype: RR Genotype: rr Genotype: rr

Phenotype: MH Phenotype: MH Phenotype: Normal Phenotype: Normal

Ruth's Father Ruth's Mother

Genotype: RR Genotype: rr

Phenotype: MH Phenotype: Normal

Brother 1 Brother 2 Ruth

Genotype: Rr Genotype: Rr Genotype: Rr

LEGEND

Female Unaffected RR: Homozygous dominant

Rr: Heterozygous

Male Unaffected

rr: Homozygous recessive

Female affected

MH: Affected with Malignant hyperthermia

Male affected Normal: Unaffected with MH Phenotype: MH Phenotype: MH Phenotype: MH

Problem 10

Assumption 1: Ruth's brother married a normal homozygous (Rr x rr)

Ruth's older brother

Gametes

R

R

Sister in-lawr

Rr

Rr

r

Rr

Rr

Probability that the child carries the mutation is ½.

(Pritchard and Bruce 2003)

Assumption 2 : Ruth's brother married a heterozygous (Rr x Rr)

Ruth's older brother

Gametes

R

R

Sister in-lawR

Rr

Rr

r

Rr

Rr

Probability that the child carries the mutation is ¾.

(Pritchard and Bruce 2003)

Problem 11

Yes, he could be susceptible to MH since IVCT result alone cannot validate the MH susceptibility. A genetic analysis testing should also be carried out to check for susceptibility even he does not inherit the mutate RYR1 gene.

(Steinfath et al. 2002)

Problem 12

Swine was used to determine the early biochemical changes with MH.

Swine and human were found to share a common biochemical basis for MH. (Solberg 1999, cited in Denborough et al., 1996).

Problem 13

Dantrolene sodium is a type of muscle relaxant that acts directly on skeletal muscle. This drug inhibits the release of calcium in the muscle cells during muscle contraction. This results in that particular muscle to be relaxed.

(Pfizer Australia Pty Ltd, 2005)

Problem 14

Dantrolene inhibits the release of Ca2t from sarcoplasmic reticulum thus directly inhibit the excitation-contraction coupling of skeletal muscle. (Rhoades and Bell 2009). A research was done in University of Minnesota by obtaining the allele of pigs that are homozygous for MH and normal RYR1 gene. Skeletal muscle sarcoplasmic reticulum vesicles were isolated from these pigs and Ca2+ released from the reticulum was observed after being treated with dantrolene. It was found that Ca2t released from both MH and normal RYR1 gene decreased. (Fruent et al. 1997)

Problem 15

Dantrolene sodium is poorly water soluble as compared to Azumolene sodium which apparently is 30-fold more soluble. (Parness and Palnitkar 1995)

Based on the structure above, these analogues differ at the middle ring, whereby, the azumolene sodium has nitrogen atom attached to it whilst absent in dantrolene sodium. Therefore, this nitrogen atom can form hydrogen bond with the aqueous environment around it and thus being more water soluble than dantrolene sodium.

Problem 16

Randomized controlled trials of treatments for MH are difficult to realize for few reasons, and one being the high technology and compliance cost the trials might incur. In order to establish the trials, more funds should also be allocated to hire specialists in many disciplines such as pathology, genetics and pharmacology. Another fundamental reason would be that MH is heavily related with the genetic history, hence one might not want to disclose his/her genetic history to public.

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