Major Metabolic Pathways of Glucose & Glucose Transport – Color Index: Important. § Extra Information. § 436 Biochemistry team Doctors slides. § Objectives: Define a metabolic pathway. Ø Describe the general metabolic pathways for Ø glucose (production and utilization). Ø Briefly describe the HMP. Ø Recognize the mechanisms of glucose transport Ø Pathway: Series of chemical reactions that have one goal. Reaction: Metabolic pathways Substrate+Substrate Product. Definition Pathway for glucose Site happens in almost every Regulatory mechanism(s) Reaction cell, starting by - Cellular tissue oxidation of glucose and 1- Rapid short-term Few are rate-limiting ending with pyruvate -Covalent modification enzymes (They are (tissue) (or lactate). -Allosteric found only in - Subcellular 2- Slow long-term irreversible Inside the cell (hormone) pathways). (Mitochondrial) -Induction\repression Metabolic pathways of glucose Catabolic Cycles Anabolic Cycles Production • Glycolysis & Gluconeogenesis Kreb (mainly) Glycogenesis • Glycogenolysis • HMP Glycogenolysis Gluco-neo- Hexose genesis interconversion To understand J *You DON’T have to know Catabolic Anabolic this* Prefix: Glyco-: glucose Glycogeno-: glycogen *except in synthesis of glycogen: we say Utilization glycogensis instead of saying glycogeno-genesis. Hexose Glyco-lysis To differentiate: the HMP / PPP interconversion Glycogenesis Catabolic Catabolic Anabolic synthesis of glucose is glucoNEOgenesis* Suffix: -genesis: process of producing Krebs cycle -lysis: breaking down. Catabolic *Aerobic: with oxygen *Anaerobic: without oxygen GLYCOLYSIS u Oxidation (breaking down) of glucose to provide energy Aerobic glyclolysis Anaerobic Aerobic glycolysis glycolysis When In absence of If there is oxygen , cells enough(adequate that lack supply) oxygen, mitochondria Cells that has mitochondria End product Lactate + 2 ATP Pyruvate(s) + 8 ATP Glycogenesis and Glycogenolysis Glycogenesis Glycogenolysis u Occurs when glucose and ATP are u Occurs in response to hormonal and present in relatively high amounts neural signals (This process is: storage) of glycogen into (ﺗﻜﺴﯿﺮ) u Degradation u Synthesis of glycogen from glucose glucose (اذا زاد اﻟﺠﻠﻮﻛﻮز ﻓﻲ اﻟﺠﺴﻢ و ﻛﺎﻧﺖ ﻛﮫﺮﺑﺎﺋﯿﺔ او (اذا اﺣﺘﺎج اﻟﺠﺴﻢ ﻳﺮﺳﻞ اﺷﺎرت اﻟﻄﺎﻗﺔ ﻣﻮﺟﻮدة ﻳﺘﻢ ﺗﺨﺰﻳﻦ اﻟﺠﻠﻮﻛﻮز ﻋﻠﻰ ھﺮﻣﻮﻧﺎت ﻟﺘﻜﺴﯿﺮ اﻟﺠﻼﻳﻜﻮﺟﯿﻦ و ﺗﺤﻮﻳﻠﻪ ﺷﻜﻞ ﺟﻼﻳﻜﻮﺟﯿﻦ ﻋﺸﺎن ﻳﺤﺮﻗﻪ و ﻟﺠﻠﻮﻛﻮز) ﻳﺴﺘﺨﺪﻣﻪ ﺑﻌﺪﻳﻦ) Both the same location: Mainly in liver and muscleà Cytosol Gluconeogenesis ﺻﻨﺎﻋﺔ اﻟﺠﻠﻮﻛﻮز ﻣﻦ ﻣﻮاد ﻏﯿﺮ اﻟﻜﺮﺑﻮھﯿﺪرات u Synthesis of glucose from non-carbohydrate precursors Precursor: is a chemical that is transformed into another compound u The precursors could be lactate (anaerobic), pyruvate (aerobic), glycerol and alpha-keto acids u It requires mitochondria and cytosolic enzymes Glycerol: is a part of the triacylglycerol u Occurs in Liver and kidney molecule which is the main constituent of body fat. Keto acids: are organic compounds that contain a carboxylic acid group and a ketone group. The alpha-keto acids are especially important in biology as they are involved in the Krebs citric acid cycle and in glycolysis. cytosolic enzymes: present in cytosol. Hexose MonoPhosphate shunt (HMP) Note: Oxidation of glucose, also Also known as Pentose Phosphate Pathway (PPP) known as glycolysis, is the process which releases energy stored in glucose by combining it with u HMP shunt is an alternative (another) pathway of glucose oxidation. oxygen. u Has the same regulatory mechanism's as glucose (rapid short-term and slow long-term) u it is not involved in the generation of energy unlike glycolysis u Around 10% of glucose (that all the body makes) is entered in this pathway. ﻓﯿﺪﻳﻮ ﻳﻠ ّﺨﺺ u In liver and kidneyà this percentage is up to 30% ﻟﻚ u Occurs in many places such as the cytosol of the liver, adipose tissue (to produce fatty acids from glucose) u Has two main functions and two phases 1- Oxidative phase 2- Non-oxidative phase 1-Provides NADPH 2- Provides Pentoses Biomedical Importance of (HMP) & (PPP) A source of NADPH NADPH is required for: 1. Synthesis of fattyacids, steroid and some Provides Pentoses for: (Pentose and its amino acids. derivatives are useful in the synthesis of: ) 2. Detoxification of drugs by (cytochrome 1. Nucleic acids (DNA and RNA ) P450 ) . 2. Nucleotides ( ATP , NAD ,FAD and CoA ) 3. In scavenging (remove) the free radicals . Note: Cytochrome P450: enzymes also function to metabolize potentially toxic compounds, including drugs and products of endogenous metabolism such as bilirubin 436 Biochemistry team From Lippincott Tissue Distribution Location of HMP: in the Cytosol of the following locations: Liver Lactating Adrenal cortex Gonads mammary glands Adipose Tissue Erythrocytes(RBC) Lens Cornea to reduce glutathione Notes J Glutathione: antioxidant capable of preventing Phases of HMP Shunt damage caused by reactive oxygen species. (Free Radicals) Cornea: the transparent layer forming the front of the eye. Non-Oxidative phase The adrenal cortex: the Oxidative phase -which provides outer part of the adrenal -which provides NADPH- gland. pentoses- Gonads: an organ that produces gametes; a testis or Oxidative phase 436 Biochemistry team Non-Oxidative phase ovary. Colors are for your understanding J Phase1: oxidative pathway The purpose of this phase is to : 1- provide 2 NADPH 2- convert Glucose6-phosphate to Ribulose 5-phospate which is an important molecule to start the next phase. Note J We start with Glucose-6-Phosphate C6H13O9P We end with Ribulose 5-phosphate C5H11O8P Ribose: aldose sugar Ribulose: Ketone sugar Phase2: non oxidative ***girls doctor said skip it A) Interconversion of pentose اﻟﮫﺪف ﻣﻨﻪ ﺳﻜﺮ ﺧﻤﺎﺳﻲ u Ribulose 5 phosphate Xylulose-5P: an intermediate in the وﺳﺪاﺳﻲ pentose phosphate :ﻳﺘﺤﻮل اﻟﻰ u pathway. It is a u Ribose 5 phosphate ketose sugar formed from ribulose-5- phosphate. These non-oxidative reversible reactions permit ribulose 5-phosphate to be converted either to ribose 5-phosphate (needed for nucleotide synthesis) or to intermediates of glycolysis—fructose 6- #ﻟﻠرﺑط: ﺗﻧطق "زي اﻟﻠوز" phosphate ّ *** .and glyceraldehyde 3-phosphate Remember that 2 important enzymes are needed in non-oxidative reactions : • 1- Transketolase, an enzyme always associated with TPP (Thiamine pyrophosphate) •TPP: a prosthetic group (is a Coenzyme associated permanently) for the Transketolase enzyme. • It is important to activate the enzyme. • 2- Transaldolase. Non Oxidative اﻟﺘﻔﺎﻋﻞ اﻻول Colors are for your (Conversion of pentose ﺗﺤﻮﻳﻞ ribulose اﻟﻰ phosphate to hexose ribose understanding J phosphate) اﻟﺘﻔﺎﻋﻞ اﻟﺜﺎﻧﻲ Ribose + xylulose ( this reaction is ﻣﮫﻢ catalyzed by Transketolase with TPP). And will give us 2 new sugar molecules : Sedoheptolose (7C) AND glyceraldehyde (3C) اﻟﺘﻔﺎﻋﻞ اﻟﺜﺎﻟﺚ Sedoheptolose +glyceraldehyde (this reaction is catalyzed by Transaldolase) And will give us 2 new sugar molecules : fructose (6C). And erythrose (4C). اﻟﺘﻔﺎﻋﻞ اﻷﺧﯿﺮ ﺗﻔﺎﻋﻼت Xylulose ﺗﻜﻮن ﻣﺼﺤﻮﺑﺔ ﺑﺈﻧﺰﻳﻢ Xylulose5-P+Erythrose4-P ( this transketolase . reaction is catalyzed by وزي ﻣﺎﻗﻠﻨﺎ ھﺎﻹﻧﺰﻳﻢ Transketolase with TPP. And will give داﻳﻤﺎ ﻳﻜﻮن ﻣﻌﺎه Note: both Glyceraldehyde TPP and fructose are us 2 sugar molecules : Fructose 6-P AND intermediates of glycolysis Glyceraldehyde 3-P . Colors are for your understanding J Phase One Phase One Enzymes numbered above are: 1, 2) glucose 6-phosphate dehydrogenase and 6-phosphogluconolactone hydrolase 3) 6-phosphogluconate dehydrogenase, 4) ribose 5-phosphate isomerase, 5) phosphopentose epimerase 6 and 8) transketolase (coenzyme: thiamine pyrophosphate) and 7) transaldolase. Extra explanation: From Lippincott Clinical Correlations G-6-PD deficiency results in : Notes J Glucose-6-phosphate dehydrogenase Heamolytic Aneamia deficiency The condition is characterized by abnormally low levels of glucose-6- phosphate dehydrogenase, an enzyme involved in the pentose phosphate pathway that is especially important in Neonatal the red blood cell. G6PD deficiency is the most common human enzyme Jaundice defect Hemolytic anemia: relating to or involving the rupture or destruction of red blood cells. Neonata: relating to newborn children Kidney failure • Tissue-specific expression Glucose Transport (GLUT 1-14) pattern Na+ 1. GLUT-1 RBCs and brain (blood-brain Monosaccharide Co- Na-Independent Facilitated Diffusion barrier) transporter: 2. GLUT-2 Liver, kidney & pancreas 1. Against 1. Down the 3. GLUT-3 Neurons concentration concentration gradient gradient 2. Energy 2. Energy- 4. GLUT-4 Adipose tissue & skeletal dependent Independent muscle 5. GLUT-5 3. Carrier-mediated 3. Glucose Small intestine & testes 4. Coupled to Na+ Transporters transport (GLUT 1-14) 6. GLUT-7 Liver (ER-membrane Boys doctor mentioned that GLUT-1, 3 & 4: Uptake of glucose from the blood. now it 20 Glucose transporters GLUT-2: Blood, cells it’s a bidirectional transporter, Note : GLUT-4 is insulin allowing glucose to flow in 2 directions. sensitive, because it GLUT-5: Fructose transport . needs insulin to work. Glucose Transport: Facilitated Diffusion 435 Teamwork: - اﻟﺠﻠﻮﻛﻮز ﻻ ﻳﺴﺘﻄﯿﻊ أن ﻳﻨﺘﺸﺮ ﺧﻼل اﻟﺨﻠﯿﺔ , ﻷﻧﻪ ﻣﺮﻛﺐ ھﺎﻳﺪروﻓﯿﻠﻚ \ ﻣﺤﺐ ﻟﻠﻤﺎء . - ﻟﺬﻟﻚ ﻓﮫﻮ ﻳﺤﺘﺎج إﻟﻰ طﺮﻳﻘﺔ أﺧﺮى , ﻓﺈﻣﺎ أن ﻳﺪﺧﻞ ﻣﻊ اﻟﺼﻮدﻳﻮم ﻋﻦ طﺮﻳﻖ اﻟﻜﻮ ﺗﺮاﻧﺴﺒﻮرت اﻟﺬي ﺳﺒﻖ أن ﺗﻌﺮﻓﻨﺎ ﻋﻠﯿﻪ ﺑﺎﻟﻔﺴﯿﻮﻟﻮﺟﻲ. - أو أﻧﻪ ﻳﺪﺧﻞ ﻋﻦ طﺮﻳﻖ ﻛﺎرﻳﺮ ﺑﺮوﺗﯿﻨﺰ ﺧﺎﺻﺔ ﺑﻪ ﺑﻄﺮﻳﻘﺔ اﻟﻔﺎﺳﯿﻠﯿﺘﺪ دﻓﯿﻮﺟﻦ واﻟﺘﻲ أﻳﻀﺎ ﺳﺒﻖ اﻟﺘﻌﺮف ﻋﻠﯿﮫﺎ ﺑﺎﻟﻔﺴﯿﻮﻟﻮﺟﻲ. (ﻣﺜﻞ اﻟﺼﻮرة) Revision Take home messages u There are multiple pathways for glucose that can be grouped in to catabolic (utilizing glucose) or anabolic (producing glucose) u Glycolysis is the major metabolic pathway of glucose breakdown to provide energy u Alternative pathway for glucose oxidation but not meant for producing energy u Has two phases- oxidative and non-oxidative u During oxidative phase, glucose-6-P is oxidized with generation of 2 moles of NADPH, and one mole of pentose phosphate, with liberation of CO2 u During non-oxidative phase, pentose phosphate is converted to intermediates of glycolysis QUIZ u Boys team members: 1- ﺣﻤﺪ اﻟﺤﺴﻮن. 2- ﻣﺤﻤﺪ ﺣﻜﻤﻲ. 3- ﺧﺎﻟﺪ اﻟﻘﺤﻄﺎﻧﻲ. :u Girls team members 4- ﺣﻤﺪ اﻟﺤﻤﯿﺪان. 5- ﻣﺤﻤﺪ ﺣﺒﯿﺐ. ﻧﻮرة اﻟﺸﺒﯿﺐ 6- ﺧﺎﻟﺪ اﻟﺮاﺟﺢ. 7- ﻓﮫﺪ اﻟﻌﺘﯿﺒﻲ. 8- طﻼل اﻟﻄﺨﯿﻢ. -Team leaders: ﻋﺒﺪﷲ اﻟﻤﺎﻧﻊ. :Contact us- ﻧﻮره اﻟﺴﮫﻠﻲ. [email protected] twitter.com/436biochemteam.