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Biochemistry-lecture notes
AMALLIA N. SETYAWATI, MD, M.SI.MED DEPT. OF MEDICAL BIOCHEMISTRY FK UNDIP
Study objectives
Increases awareness of Nutrition, Metabolism, and
Temperature Regulation with respect to Krebs cycle Understand: -basic principles of Krebs cycle Underlying principles in Krebs cycle with pursuant to metabolic regulation Application of Krebs cycle in clinical setting & human milieu system Establish foundation to facilitate further pursuance in related subject matter either in laboratory (research) or clinical context
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Biochemistry. Lange Medical Books/McGrawHill.26th ed.2003:130 2. Lehninger: Principles of biochemistry USEFUL SITES: 1. http://highered.mcgrawhill.com/sites/0072507470/student_view0/chapte r25/animation__how_the_krebs_cycle_works 2. http://www.wiley.com/college/pratt/0471393878/ student/animations/citric_acid_cycle/index.html
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PRE-SEMESTER & will be highlighted in Clinical relevancy of Krebs cyle Medical biochemistry knowledge in Krebs cyle UKDI (competence skills assesment for medical doctor ~ Krebscyle) 80% of the exam questions will be relevant to this lecture notes & supplementary hand-out, the rest will be testing on your self-reading on the refference below
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Class organization:
Please prepare a paper sheet & write with NAME
and NIM This paper sheet will also be considered as a student presence notification Prepare for the quizzes during the next 50 minutes lect In the end of this class, the paper sheets shall be collected In any term, the students whom do not collect the papers will be regarded as ABSENT
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Biomedical importance
Reactions of the Citric Acid Cycle Citric acid cycle role in metabolism
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If citrate is added the rate of respiration is often increased . . . the extra oxygen uptake is by far greater than can be accounted for by the complete oxidation of citrate . . . Since citric acid reacts catalytically in the tissue it is probable that it is removed by a primary reaction but regenerated by a subsequent reaction. H. A. Krebs and W. A. Johnson, article in Enzymologia, 1937
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discovering the cycle. Sir Krebs outlined the steps of the cycle in 1937.
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INTRODUCTION
Krebs cycle citric acid cycle, tricarboxylic acid
Location mitochondria
Krebs cycle reaction:
1. oxidize acetyl residues (as acetyl-CoA) 2. reduce coenzymes that upon reoxidation are linked to the formation of ATP.
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degradation or synthesis of large molecules CATABOLISM reactions that breakdown molecules ANABOLISM reactions that synthesize
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The citric acid cycle serves two main purposes: To increase the cells ATP-producing potential by generating a reduced electron carriers such as NADH and reduced ubiquinone; and To provide the cell with a variety of metabolic precursors. 7/26/2010
glycolysis
Cell organization
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final oxidant of the reduced coenzymes. The enzymes of the citric acid cycle are located cated in the mitochondrial matrix, either free or attached to the inner mitochondrial membrane, where the enzymes of the respiratory chain are also found.
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BIOMEDICAL IMPORTANCE
The final common pathway aerobic oxidation of
carbohydrate, lipid, and protein because glucose, fatty acids, and most amino acids etabolized to acetyl-CoA or intermediates of A central role in gluconeogenesis,lipogenesis, and interconversion of amino acids. Mostly these reactions can tak e place in all tissue but only liver which can extend the process Thus in any condition of large numbers of hepatic cells are damaged as in acute hepatitis or replaced by connective tissue (as in cirrhosis).
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the acetyl-CoA + the four-carbon oxaloacetate (4 C) Forming a six-carbon tricarboxylic acid, citrate. In the subsequent reactions, two molecules of CO2 are released and oxaloacetate is regenerated. A small quantity of oxaloacetate oxidation of a large quantity of acetyl-CoA; oxaloacetate may be considered to play a catalytic role.
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which much of the free energy liberated during the Oxidation of fuels is made available. During oxidation of acetyl-CoA, coenzymes are reduced and subsequently reoxidized in the respiratory chain, linked to the formation. Krebs cycle is an ACTIVE & FULLY-REGULATED process in the cell.
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1. Oxidized acetyl CoA CO2, H2O dan E! (1 mol acetyl CoA releases 12 mol ATP this cycle releases abundant H+ & electron which will enter respiratory cycle) 2. TCA cycle members are amphibolic : can be further oxidized to become E! or synthesized to another compounds
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Merupakan reaksi kondensasi aldol yg disertai hidroli sis dan berjalan searah Tahap 2 Sitrat diubah menjadi isositrat oleh enzim akonitase yg mengandung Fe++ caranya : mula2 terjadi dehidrasi menjadi cis-akonitat ( yg tetap terikat enzim ) kemudian terjadi rehidrasi menjadi isositrat
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Tahap 3
zim) oleh isositrat dehidrogenase yg memerlukan NAD+ Reaksi ini diikuti dekarboksilasi oleh enzim yg sama menjadi -ketoglutarat. Enzim ini memerlukan Mn++ / Mg++ Ada 3 jenis isozim isositrat dehidrogenase : * satu jenis isozim menggunakan NAD+ isozim ini hanya ditemukan di dalam mitokondria NADH + H+ yg terbentuk akan diteruskan dalam rantai respirasi * Dua jenis isozim yg lain menggunakan NADP+ dan Setyawati AN (2010) ditemukan dalam mitokondria dan sitosol 7/26/2010
Tahap 4
ti pada dekarboksilasi oksidatif piruvat) menjadi suksi nil KoA oleh enzim -ketoglutarat dehidrogenase kom pleks Enzim ini memerlukan kofaktor seperti : TPP, Lipoat, NAD+, FAD dan KoA-SH
Reaksi ini secara fisiologis berjalan searah Reaksi ini dapat dihambat oleh arsenit
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Tahap 5
Suksinat thikonase
Suksinil KoA
Suksinat Reaksi ini memerlukan ADP atau GDP yg dengan Pi akan membentuk ATP atau GTP. Juga memerlukan Mg++ Reaksi ini merupakan satu2nya dalam TCA cycle yg membentuk senyawa fosfat berenergi tinggi pada tingkat substrat Pada jaringan dimana glukoneogenesis terjadi ( hati & ginjal) terdapat 2 jenis isozim suksinat thiokonase, satu jenis spesifik GDP, satu jenis untuk ADP. Pada jaringan nonglukoneogenik hanya ada isozim yg menggunakan ADP
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Tahap 6
Suksinat dehidrogenase
Suksinat + FAD Fumarat + FADH2 Reaksi ini tdak lewat NAD, dihambat oleh malonat Tahap 7 Fumarase Fumarat + H2O L-Malat Tahap 8 Malat dehidrogenase L-Malat + NAD+ Oksaloasetat + NADH + H+ Reaksi ini membentuk kembali oksaloasetat
Reaksi total :
Asetil KoA + 3NAD+ + FAD + ADP (atau GDP) + Pi + H2O 2CO2 + KoA-SH + 3 NADH + 3 H+ + FADH2 + ATP AN (2010) GTP) ( atau Setyawati 7/26/2010
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LIHAT GAMBAR SIKLUS ASAM SITRAT REAKSI DEHIDROGENASE * yg menggunakan NAD+ 3 ATP * yg menggunakan FAD (tak lewat NAD+) 2 ATP Suksinat thikonase : 1 ATP atau 1 GTP Reaksi yg menghasilkan CO2 ( dekarboksilasi oksidatif) : reaksi yg dikatalisis oleh isositrat dehidrogenase dan -ketoglutarat dehidrogenase kompleks Vitamin B yg berperan pada TCA cycle sbg bentuk koenzimnya : Thiamin TPP Niacin NAD Riboflavin FAD Asam pantotenat KoA
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kan : * 3 mol (NADH + H+) yg akan masuk rantai respirasi menghasilkan 3 x 3 mol ATP = 9 mol AP * 1 mol FADH2 yg akan masuk rantai respirasi menghasilkan 2 mol ATP * Enzim suksinat thiokinase menghasilkan 1 mol ATP ( atau GTP ) * Jadi dari 1 mol asetil KoA dihasilkan 12 mol senyawa fosfat berenergi tinggi
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INHIBITOR SIKLUS ASAM SITRAT Fluoroasetat : * Dgn KoA-SH membentuk fluoroasetil-KoA * Fluoroasetil-KoA berkondensasi dgn oksaloasetat membentuk fluorositrat ( dikatalisis oleh sitrat sintase) * Fluorositrat menghambat akonitase terjadi akumulasi sitrat * Fluoroasetat didapatkan misalnya pada pestisida
Malonat : menghambat suksinat dehidrogenase
kompleks
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nonruminants Acetyl CoA made by pruvate dehydrogenase enzymes cannot cross mitochondria membran, Therefore novice citrate cytosol ATP-sitrat liase enzym acetyl CoA FA in cytosol
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CLINICAL PRESPECTIVES
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mitochondrion
THANK YOU !
Shall you have any query regarding to this lecture, please do not hessitate to mail : dramallia@undip.ac.id
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